Methods of using cycloalkylmethylamines

ABSTRACT

The present invention provides novel cycloalkylmethylamine analogs, and methods of preparing cycloalkylmethylamine analogs. The present invention also provides methods of using cycloalkylmethylamine analogs and compositions of cycloalkylmethylamine analogs. The pharmaceutical compositions of the compounds of the present invention can be advantageously used for treating and/or preventing obesity and obesity related co-morbid indications.

CROSS REFERENCE OF RELATED APPLICATIONS

The present application is a divisional application of U.S. patentapplication Ser. No. 11/856,670, filed on Sep. 17, 2007, which claimsthe benefit of U.S. Provisional Application Ser. No. 60/825,868, filedon Sep. 15, 2006, which are incorporated herein by reference in theirentirety.

1. FIELD OF THE INVENTION

The present invention relates to cycloalkylmethylamines, synthesis ofcycloalkylmethylamines and methods of using cycloalkylmethylamines forthe pharmacological treatment of obesity and obesity related co-morbidindications.

2. BACKGROUND OF THE INVENTION

Obesity is a chronic disease that affects millions of people across theworld especially in the developed countries. It is defined by excessbody fat and is generally measured by calculating a person's BMI (bodymass index). If a person's BMI is 30 or above, he or she considered tobe obese. Obesity can cause a number of health problems either directlyor indirectly, such as, for example, type 2 diabetes, coronary heartdisease, high blood triglycerides, high blood pressure and stroke.Obesity also raises risk of certain types of cancer. Obese men are morelikely than normal-weight peers to die from cancer of the colon, rectum,and prostate. Obese women are more likely than non-obese women to diefrom cancer of the gallbladder, breast, uterus, cervix and ovaries.Death from some cancers may be more likely because obesity makes thecancers harder to detect in the early stages (for example, the initialsmall lump of breast cancer may not be felt in an obese woman). Recentstudies show obesity increases the risk of Alzheimer's-type dementia.Other disease and health problems linked to obesity include: gallbladderdisease, gallstones, osteoarthritis, gout or joint pain, sleep apnea,psychological and social problems.

Obesity is caused by multiple factors, the primary factor being geneticswhich is the one factor relating to obesity over which individuals haveno control. Other important factors involved in obesity are: themechanisms of fat storage; the balance between energy intake and energyexpenditure; an individual's life style: eating habits and exercise; andpsychological, cultural and socioeconomic influences. Despite theseeming inexorable progression of this disease, there have been limitedadvances in the pharmacotherapy of this condition. Drugs to treatobesity can be divided into three groups: those that reduce food intakeor appetite suppressants; those that alter metabolism or block theabsorption of fat; and those that increase thermogenesis. Currently,there are only two drugs approved by the FDA for the long-term treatmentof obesity and they are fat absorption blocker orlistat (XENICAL®) andthe appetite suppressant sibutramine (MERIDIA®). The only thermogenicdrug combination that has been tested is ephedrine and caffeine, butthis treatment has not been approved by regulatory agencies.

The fat absorption blocker, orlistat works in the gastrointestinal tractby blocking an enzyme that is needed to digest fat. Instead of beingabsorbed from the intestine, up to one-third of the fat that a personconsumes is excreted in the stool. In addition, orlistat blocks theabsorption of needed fat-soluble vitamins A, D, E, and K, as well asbeta-carotene. This is one of the major limitations of this drug for thelong term use in the treatment of obesity. Most commonly reported otherside effects of orlistat are bloating, diarrhea and oily stools.

In the appetite suppressant category, a few noradrenergic andserotonergic drugs belong to a family of 2-arylethylamines are currentlyavailable in the market for the treatment of obesity. The noradrenergicagents such as phenylpropanolamine, (ACUTRIM®, DEXATRIM®),diethylpropion (TENUATE®), and phentermine (FASTIN®), IONAMIN®) areapproved for the short-term treatment of obesity. Whereas, noradrenergicand serotonergic agent sibutramine (MERIDIA®) is the only drug currentlyapproved for the long-term treatment of obesity in the appetitesuppressant category. Sibutramine has cyclobutanemethylamine backboneand it is this backbone mainly responsible for its uniquepharmacological properties.

In the last 10 years, a number of reports have been published on thepossible use of sibutramine, either alone or in combination with othertherapeutic agents, for the treatment and/or prevention of a varietydiseases and/or disorders in addition to obesity (see, Montana, J. G.International Application Publication No. WO 2004/058237; Lulla, A. etal., International Application Publication No. WO 2004/096202; Jerussi,T. P. et al., International Application Publication No. WO 02/060424;Senanayake, C. H. et al., International Application Publication No. WO01/51453; Heal, D. J. International Application Publication No. WO01/00205; Birch, A. M. et al., International Application Publication No.WO 01/00187; Mueller, P. International Application Publication No. WO00/32178; Bailey, C. International Application Publication No. WO98/11884; Kelly, P. International Application Publication No. WO98/13034). For examples: treatment of nausea, emesis, and relatedconditions; cognitive dysfunctions; eating disorders; weight gain;irritable bowel syndrome; obsessive compulsive disorders; plateletadhesion; apnea, affective disorders such as attention deficitdisorders, depression, and anxiety; male and female sexual functiondisorders; restless leg syndrome; osteoarthritis; substance abuseincluding nicotine and cocaine addiction; narcolepsy; pain such asneuropathic pain, diabetic neuropathy, and chronic pain; migraines;cerebral function disorders; chronic disorders such as premenstrualsyndrome; and incontinence.

In general, sibutramine has a number of therapeutic benefits because ofits unique pharmacological properties. However, sibutramine'stherapeutic use for the treatment of obesity, and other diseases anddisorders is currently not fully utilized because of certain limitationsand adverse side effects associated with the drug. The major adverseevents reported, in some cases life threatening, include increase inblood pressure and the side effects derived from the drug-druginteractions, for example, serotonin syndrome. The majority of theseadverse events are, to some extent, metabolism-based. Sibutramine exertsits pharmacological actions predominantly via its secondary (M₁) andprimary (M₂) amine metabolites. Sibutramine is metabolized in the liverprincipally by the cytochrome P450 (3A4) isozymes, to desmethylmetabolites, M₁ and M₂. These active metabolites are further metabolizedby hydroxylation and conjugation to pharmacologically inactivemetabolites, M₅ and M₆. The elimination half-lives of therapeuticallyactive primary and secondary metabolites M₁ and M₂ are 14 and 16 hours,respectively. It is evident from a number literature reports thatcytochrome P450 mediated metabolism and the long half lives of activemetabolites (M₁ and M₂) are to a great extent responsible for adverseevents such as increased blood pressure and other side effects derivedfrom drug-drug interactions of sibutramine.

Therefore, there is a need and great demand for safer and effective nextgeneration appetite suppressants for the treatment of obesity. An idealdrug in this class should have potent appetite suppressant activity, aproven effect on fat loss, be well tolerated during acute and chronicadministration and have alleviated side effects when compared tosibutramine and phentermine.

3. SUMMARY OF THE INVENTION

The present invention is directed towards compositions of novelcycloalkylmethylamine analogs and the use of the compositions for thetreatment of obesity and related co-morbid conditions. The presentinvention provides methods for synthesizing such cycloalkylmethylamineanalogs. The present invention also provides methods for usingcycloalkylmethylamine analogs, and pharmaceutical composition ofcycloalkylmethylamine analogs for treating or preventing obesity andco-morbid diseases and/or disorders.

The compounds of the subject invention provide next generationnoradrenergic and serotonergic active appetite suppressants, and areparticularly effective and safe for the treatment of obesity andco-morbid diseases and/or disorders. They are advantageous because oftheir favorable metabolic, pharmacokinetics and pharmacologicalprofiles. Specifically, these compounds are primarily metabolized byhydrolytic enzymes not by cytochrome P450 enzymes. These compounds havea highly predictable pharmacokinetic profile and are particularlyadvantageous because their metabolites have reduced systemic exposure incomparison to the active drug.

In one aspect, the present invention provides cycloalkylmethylaminederivatives comprising compounds of structural Formula (I):

or a pharmaceutically acceptable salts, hydrates or solvates thereofprovided that the compounds of the invention comprise a soft-moietyconjugated directly or via a spacer on one of the substituents R¹, R²,and R³; wherein:

n is 0, 1, 2, 3, 4, or 5;

R¹ and R² are independently selected to be hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,or substituted heteroarylalkyl, or optionally R¹ and R² together withthe atoms to which R¹ and R² are attached, form a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkylring which is optionally fused to an aryl, substituted aryl, heteroaryl,substituted heteroaryl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring;

R³ can be selected to be hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, or substitutedheteroarylalkyl; and

R⁴ can be selected to be hydrogen, alkyl, or substituted alkyl.

4. DETAILED DESCRIPTION OF THE INVENTION

This invention provides compounds, pharmaceutical compositions andmethods for pharmacological treatment of obesity and related co-morbiddiseases and/or disorders. This invention also provides methods forsynthesis of novel appetite suppressants which are predominantlymetabolized by hydrolytic enzymes. However, prior to describing thisinvention in further detail, the following terms will be first defined.

4.1 Definitions

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Definition ofstandard chemistry terms may be found in reference works, includingCarey and Sundberg (1992) “Advanced Organic Chemistry 3^(rd) Ed.” Vols.A and B, Plenum Press, New York. The practice of the present inventionwill employ, unless otherwise indicated, conventional methods of massspectroscopy, protein chemistry, biochemistry, recombinant DNAtechniques and pharmacology, within the skill of the art. Thecompositions and formulations described herein can be practicedemploying the pharmaceutically acceptable excipients and salts availablein Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pa.: MackPublishing Company, 1990).

“Compounds of the invention” refers to compounds encompassed bystructural Formulae (I) to (IV) disclosed herein, and includes anyspecific compounds within these Formulae whose structure is disclosedherein. The compounds of the invention may be identified either by theirchemical structure and/or chemical name. When the chemical structure andchemical name conflict, the chemical structures is determinative of theidentity of the compound. The compounds of the invention may contain oneor more chiral centers and/or double bonds and therefore, may exist asstereoisomers, such as double-bond isomers (i.e., geometric isomers),enantiomers or diastereoisomers. Accordingly, the chemical structuresdepicted herein encompass all possible enantiomers and stereoisomers ofthe illustrated compounds including the stereoisomerically pure form(e.g., geometrically pure, enantiomerically pure or diastereomericallypure) and enantiomeric and stereoisomeric mixtures. Enantiomeric andstereoisomeric mixtures can be resolved into their component enantiomersor stereoisomers using separation techniques or chiral synthesistechniques well known to the skilled artisan. The compounds of theinvention may also exist in several tautomeric forms including the enolform, the keto form and mixtures thereof. Accordingly, the chemicalstructures depicted herein encompass all possible tautomeric forms ofthe illustrated compounds. The compounds of the invention also includeisotopically labeled compounds where one or more atoms have an atomicmass different from the atomic mass of conventionally found in nature.Examples of isotopes that may be incorporated into the compounds of theinvention include, but are not limited to ²H, ³H, ¹³C, ¹⁵N, ¹⁸O, ¹⁷O,³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl. Further, it should be understood, whenpartial structures of the compounds of the invention are illustrated,that brackets of dashes indicate the point of attachment of the partialstructure to the rest of the molecule.

“Composition of the invention” refers to at least one compound of theinvention and a pharmaceutically acceptable vehicle, with which thecompound is administered to a patient. When administered to a patient,the compounds of the invention are administered is isolated form, whichmeans separated from a synthetic organic reaction mixture.

“Alkyl” refers to a saturated or unsaturated, branched, straight-chainor cyclic monovalent hydrocarbon radical derived by the removal of onehydrogen atom from a single carbon atom of a parent alkane, alkene oralkyne. Typical alkyl groups include, but are not limited to methyl;ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl,propan-2yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl (allyl), cycloprop-1-en-1yl, cycloprop-2-en-1yl,prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl,butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl-buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

The term “alkyl” specifically intended to include radicals having anydegree or level of saturation, i.e., groups having exclusively singlecarbon-carbon bonds, groups having one or more double carbon-carbonbonds, groups having one or more triple carbon-carbon bonds and groupshaving mixtures of single, double and triple carbon-carbon bonds. Wherea specific level of saturation is intended, the expressions “alkanyl,”“alkenyl,” and “alkynyl,” are used. Preferably, an alkyl group comprisesfrom 1-20 carbon atoms, more preferably, from 1 to 10 carbon atoms.

“Alkanyl” refers to a saturated branched, straight-chain or cyclic alkylradical derived by the removal of one hydrogen atom from a single carbonatom of a parent alkane. Typical alkanyl groups include but are notlimited to, methanyl; ethanyl; propanyls such as propan-1-yl,propan-2-yl (isopropyl), cyclopropan-1-yl, etc.; butanyls such asbutan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl),2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like.

“Alkenyl” refers to an unsaturated branched, straight-chain or cyclicalkyl radical having at least one carbon-carbon double bond derived bythe removal of one hydrogen atom from a single carbon atom of a parentalkene. The group may be in either the cis or trans conformation aboutthe double bond(s). Typical alkenyl groups include, but are not limitedto, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl,cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl,2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl,cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the like.

“Alkynyl” refers to an unsaturated branched, straight-chain or cyclicalkyl radical having at least one carbon-carbon triple bond derived bythe removal of one hydrogen atom from a single carbon atom of a parentalkyne. Typical alkynyl groups include, but are not limited to, ethynyl;propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such asbut-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

“Acyl” refers to a radical —C(O)R, where R is hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, as defined herein that may be optionally substituted asdefined herein. Representative examples include, but are not limited toformyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl,benzylcarbonyl and the like.

“Acyloxyalkyloxycarbonyl” refers to a radical —C(O)OR′R″OC(O)R′″, whereR′, R″, and R′″ are each independently hydrogen, alkyl, cycloalkyl,cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, as defined herein that may be optionally substituted asdefined herein. Representative examples include, but not limited to—C(O)OCH₂OC(O)CH₃, —C(O)OCH₂OC(O)CH₂CH₃, —C(O)OCH(CH₃)OC(O)CH₂CH₃,—C(O)OCH(CH₃)OC(O)C₆H₅ and the like.

“Acylalkyloxycarbonyl” refers to a radical —C(O)OR′R″C(O)R′″, where R′,R″, and R″ are each independently hydrogen, alkyl, cycloalkyl,cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, as defined herein that may be optionally substituted asdefined herein. Representative examples include, but not limited to—C(O)OCH₂C(O)CH₃, —C(O)OCH₂C(O)CH₂CH₃, —C(O)OCH(CH₃)C(O)CH₂CH₃,—C(O)OCH(CH₃)C(O)C₆H₅ and the like.

“Acyloxyalkyloxycarbonylamino” refers to a radical —NRC(O)OR′R″OC(O)R′″,where R, R′, R″, and R′″ are each independently hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, as defined herein that may be optionally substituted asdefined herein. Representative examples include, but not limited to—NHC(O)OCH₂OC(O)CH₃, —NHC(O)OCH₂OC(O)CH₂CH₃, —NHC(O)OCH(CH₃)OC(O)CH₂CH₃,—NHC(O)OCH(CH₃)OC(O)C₆H₅ and the like.

“Acylalkyloxycarbonylamino” refers to a radical —NRC(O)OR′R″C(O)R′″,where R, R′, R″, and R′″ are each independently hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, as defined herein that may be optionally substituted asdefined herein. Representative examples include, but not limited to—NHC(O)OCH₂C(O)CH₃, —NHC(O)OCH₂C(O)CH₂CH₃, —NHC(O)OCH(CH₃)C(O)CH₂CH₃,—NHC(O)OCH(CH₃)C(O)C₆H₅ and the like.

“Acylamino” refers to “Amide” as defined herein.

“Alkylamino” means a radical —NHR where R represents an alkyl, orcycloalkyl group as defined herein that may be optionally substituted asdefined herein. Representative examples include, but are not limited to,methylamino, ethylamino, 1-methylethylamino, cyclohexylamino and thelike.

“Alkoxy” refers to a radical —OR where R represents an alkyl, orcycloalkyl group as defined herein that may be optionally substituted asdefined herein. Representative examples include, but are not limited tomethoxy, ethoxy, propoxy, butoxy, cyclohexyloxy and the like.

“Alkoxycarbonyl” refers to a radical —C(O)-alkoxy where alkoxy is asdefined herein.

“Alkoxycarbonylalkoxy” refers to a radical —OCR′R″C(O)-alkoxy wherealkoxy is as defined herein. Similarly, where R′ and R″ are eachindependently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined hereinthat may be optionally substituted as defined herein. Representativeexamples include, but are not limited to —OCH₂C(O)OCH₃,—OCH₂C(O)OCH₂CH₃, —OCH(CH₃)C(O)OCH₂CH₃, —OCH(C₆H₅)C(O)OCH₂CH₃,—OCH(CH₂C₆H₅)C(O)OCH₂CH₃, —OC(CH₃)(CH₃)C(O)OCH₂CH₃, and the like.

“Alkoxycarbonylalkylamino” refers to a radical —NRCR′R″C(O)-alkoxy wherealkoxy is as defined herein. Similarly, where R, R′, R′ and R″ are eachindependently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined hereinthat may be optionally substituted as defined herein. Representativeexamples include, but are not limited to —NHCH₂C(O)OCH₃,—N(CH₃)CH₂C(O)OCH₂CH₃, —NHCH(CH₃)C(O)OCH₂CH₃, —NHCH(C₆H₅)C(O)OCH₂CH₃,—NHCH(CH₂C₆H₅)C(O)OCH₂CH₃, —NHC(CH₃)(CH₃)C(O)OCH₂CH₃, and the like.

“Alkylsulfonyl” refers to a radical —S(O)₂R where R is an alkyl, orcycloalkyl group as defined herein that may be optionally substituted asdefined herein. Representative examples include, but are not limited to,methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, and thelike.

“Alkylsulfinyl” refers to a radical —S(O)R where R is an alkyl, orcycloalkyl group as defined herein that may be optionally substituted asdefined herein. Representative examples include, but are not limited to,methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, and thelike.

“Alkylthio” refers to a radical —SR where R is an alkyl or cycloalkylgroup as defined herein that may be optionally substituted as definedherein. Representative examples include, but are not limited tomethylthio, ethylthio, propylthio, butylthio, and the like.

“Amide or Acylamino” refers to a radical —NR′C(O)R″, where R′ and R″ areeach independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined hereinthat may be optionally substituted as defined herein. Representativeexamples include, but are not limited to, formylamino acetylamino,cyclohexylcarbonylamino, cyclohexylmethylcarbonyl-amino, benzoylamino,benzylcarbonylamino and the like.

“Amino” refers to the radical —NH₂

“Aryl” refers to a monovalent aromatic hydrocarbon radical derived bythe removal of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Typical aryl groups include, but are not limitedto, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorine, hexacene, hexaphene, hexylene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleidene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene, and the like. Preferable, anaryl group comprises from 6 to 20 carbon atoms, more preferably, between6 to 12 carbon atoms.

“Arylalkyl” refers to an acyclic alkyl in which one of the hydrogenatoms bonded to a carbon atom, typically a terminal or sp³ carbon atom,is replaced with an aryl group. Typically arylalkyl groups include, butnot limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl,naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethene-1-yl,naphthobenzyl, 2-naphthophenylethan-1-yl and the like. Where specificalkyl moieties are intended, the nomenclature arylalkany, arylalkenyland/or arylalkynyl is used. Preferably, an arylalkyl group is(C₆-C₃₀)arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of thearylalkyl group is (C₁-C₁₀) and the aryl moiety is (C₆-C₂₀), morepreferably, an arylalkyl group is (C₆-C₂₀) arylalkyl, e.g., the alkanyl,alkenyl or alkynyl moiety of the arylalkyl group is (C₁-C₈) and the arylmoiety is (C₆-C₁₂).

“Arylalkoxy” refers to an —O-arylalkyl radical where arylalkyl is asdefined herein that may be optionally substituted as defined herein.

“Arylalkoxycarbonylalkoxy” refers to a radical —OCR′R″C(O)-arylalkoxywhere arylalkoxy is as defined herein. Similarly, where R′ and R″ areeach independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined hereinthat may be optionally substituted as defined herein. Representativeexamples include, but are not limited to —OCH₂C(O)OCH₂C₆H₅,—OCH(CH₃)C(O)OCH₂C₆H₅, —OCH(C₆H₅)C(O)O CH₂C₆H₅,—OCH(CH₂C₆H₅)C(O)OCH₂C₆H₅, —OC(CH₃)(CH₃)C(O)OCH₂C₆H₅, and the like.

“Arylalkoxycarbonylalkylamino” refers to a radical—NRCR′R″C(O)-arylalkoxy where arylalkoxy is as defined herein.Similarly, where R, R′, R′ and R″ are each independently hydrogen,alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl,heteroaryl, heteroarylalkyl, as defined herein that may be optionallysubstituted as defined herein. Representative examples include, but arenot limited to —NHCH₂C(O)OCH₂C₆H₅, —N(CH₃)CH₂C(O)OCH₂C₆H₅,—NHCH(CH₃)C(O)OCH₂C₆H₅, —NHCH(C₆H₅)C(O)OCH₂C₆H₅,—NHCH(CH₂C₆H₅)C(O)OCH₂C₆H₅, —NHC(CH₃)(CH₃)C(O)OCH₂C₆H₅, and the like.

“Aryloxycarbonyl” refers to radical —C(O)—O-aryl where aryl is definedherein that may be optionally substituted as defined herein.

“Aryloxycarbonylalkoxy” refers to a radical —OCR′R″C(O)-aryloxy wherearyloxy is as defined herein. Similarly, where R′ and R″ are eachindependently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined hereinthat may be optionally substituted as defined herein. Representativeexamples include, but are not limited to —OCH₂C(O)OC₆H₅,—OCH(CH₃)C(O)OC₆H₅, —OCH(C₆H₅)C(O)OC₆H₅, —OCH(CH₂C₆H₅)C(O)OC₆H₅,—OC(CH₃)(CH₃)C(O)OC₆H₅, and the like.

“Aryloxycarbonylalkylamino” refers to a radical —NRCR′R″C(O)-aryloxywhere aryloxy is as defined herein. Similarly, where R, R′, R′ and R″are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl,aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as definedherein that may be optionally substituted as defined herein.Representative examples include, but are not limited to —NHCH₂C(O)OC₆H₅,—N(CH₃)CH₂C(O)OC₆H₅, —NHCH(CH₃)C(O)OC₆H₅, —NHCH(C₆H₅)C(O)OC₆H₅,—NHCH(CH₂C₆H₅)C(O)OC₆H₅, —NHC(CH₃)(CH₃)C(O)OC₆H₅, and the like.

“Carbamoyl” refers to the radical —C(O)N(R)₂ where each R group isindependently, hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined hereinthat may be optionally substituted as defined herein.

“Carbamate” refers to a radical —NR′C(O)OR″, where R′ and R″ are eachindependently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined hereinthat may be optionally substituted as defined herein. Representativeexamples include, but are not limited to, methylcarbamate (—NHC(O)OCH₃),ethylcarbamate (—NHC(O)OCH₂CH₃), benzylcarbamate (—NHC(O)OCH₂C₆H₅), andthe like.

“Carbonate” refers to a radical —OC(O)OR, where R is alkyl, cycloalkyl,cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, as defined herein that may be optionally substituted asdefined herein. Representative examples include, but are not limited to,methyl carbonate (—C(O)OCH₃), cyclohexyl carbonate (—C(O)OC₆H₁₁), phenylcarbonate (—C(O)OC₆H₅), benzyl carbonate (—C(O)OCH₂C₆H₅), and the like.

“Carboxy” means the radical —C(O)OH.

“Cyano” means the radical —CN.

“Cycloalkyl” refers to a substituted or unsubstituted cyclic alkylradical. Where a specific level of saturation is intended, thenomenclature “cycloalkanyl” or “cycloalkenyl” is used. Typicalcycloalkyl groups include, but are not limited to, groups derived fromcyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. In apreferred embodiment, the cycloalkyl group is (C₃-C₁₀) cycloalkyl, morepreferably (C₃-C₇) cycloalkyl.

“Cycloheteroalkyl” refers to a saturated or unsaturated cyclic alkylradical in which one or more carbon atoms (and any associated hydrogenatoms) are independently replaced with the same or different heteroatom.Typical heteroatoms to replace the carbon atom(s) include, but are notlimited to, N, P, O, S, Si, etc. Where a specific level of saturation isintended, the nomenclature “cycloheteroalkanyl” or “cycloheteroalkenyl”is used. Typical cycloheteroalkyl groups include, but are not limitedto, groups derived from epoxides, imidazolidine, morpholine, piperazine,piperidine, pyrazolidine, pyrrolidine, quinuclidine, and the like.

“Cycloheteroalkoxycarbonyl” refers to a radical —C(O)—OR where R iscycloheteroalkyl as defined herein.

“Dialkylamino” means a radical —NRR′ where R and R′ independentlyrepresent an alkyl or cycloalkyl group as defined herein. Representativeexamples include, but are not limited to dimethylamino,methylethylamino, di-(1-methylethyl)amino, (cyclohexyl)(methyl)amino,(cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino, and the like.

“Derived from a drug” refers to a fragment that is structurally relatedto such a drug. The structure of the fragment is identical to the drugexcept where a hydrogen atom attached to a heteroatom (N or O) has beenreplaced with a covalent bond to another group (typically, a promoiety).Note that when a drug is a salt form of a carboxylic, phosphonic orphosphoric acid, the corresponding structural fragment derived from sucha drug is considered to derived from the protonated acid form.

“Drug” refers to a compound that exhibits therapeutic and/orprophylactic and/or diagnostic utility when administered in effectiveamounts to a patient or a mammal.

“Ester” refers to a radical —C(O)OR, where R is alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl as definedherein. Representative examples include, but are not limited to, methylester (—C(O)OCH₃), cyclohexyl ester (—C(O)OC₆H₁₁), phenyl ester(—C(O)OC₆H₅), benzyl ester (—C(O)OCH₂C₆H₅), and the like.

“Halo” means fluoro, chloro, bromo, or iodo.

“Heteroalkoxy” means an —O-heteroalkyl radical where heteroalkyl is asdefined herein.

“Heteroalkyl, Heteroalkanyl, Heteroalkenyl, Heteroalkynyl” refer toalkyl, alkanyl, alkenyl and alkynyl groups, respectively, in which oneor more of the carbon atoms (and any associated hydrogen atoms) are eachindependently replaced with the same or different heteroatomic groups.Typical heteroatomic groups include, but are not limited to —O—, —S—,—O—O—, —S—S—, —OS—, —NR′—, ═N—N═, —N═N—, —N═N—NR′—, —PH—, —P(O)₂—,—O—P(O)—, —S(O—, —S(O)₂—, —SnH₂—, and the like, wherein R′ is hydrogen,alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl orsubstituted aryl.

“Heteroaryl” refers to a monovalent heteroaromatic radical derived bythe removal of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Typical heteroaryl groups include, but arenot limited to, groups derived from acridine, arsindole, carbazole,carboline, chromane, chromene, cinnoline, furan, imidazole, indazole,indole, indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene, and the like. Preferably, the heteroarylgroup is between 5-20 membered heteroaryl, with 5-10 membered heteroarylbeing particularly preferred. Preferred heteroaryl groups are thosederived from thiophene, pyrrole, benzothiophene, benzofuran, indole,pyridine, quinoline, imidazole, oxazole and pyrazine.

“Heteroaryloxycarbonyl” refers to a radical —C(O)—OR where R isheteroaryl as defined.

“Heteroarylalkyl” refers to an acyclic alkyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp3carbon atom, is replaced with a heteroaryl group. Where specific alkylmoieties are intended, the nomenclature heteroarylalkanyl,heteroarylalkenyl and/or heteroarylalkynyl is used. Preferably, theheteroarylalkyl radical is a 6-30 carbon membered heteroarylalkyl, e.g.,the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-10membered and the heteroaryl moiety is a 5-20 membered heteroaryl, morepreferably, a 6-20 membered heteroarylalkyl, e.g., the alkanyl, alkenylor alkynyl moiety of the heteroarylalkyl is 1-8 membered and theheteroaryl moiety is a 5-12 membered heteroaryl.

“Hydroxy” means the radical —OH.

“Oxo” means the divalent radical ═O.

As used herein, the term “patient” encompasses mammals and non-mammals.Examples of mammals include, but are not limited to, any member of theMammalian class: humans, non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice and guineapigs, and the like. Examples of non-mammals include, but are not limitedto, birds, fish and the like. The term does not denote a particular ageor gender.

“Pharmaceutically acceptable” means approved or approvable by aregulatory agency of the Federal or state government or listed in theU.S. Pharmacopoeia or other generally recognized pharmacopoeia for usein animals, and more particularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of theinvention, which is pharmaceutically acceptable and possesses thedesired pharmacological activity of the parent compound. Such saltsinclude: (1) acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentane propionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2,2,2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound isreplaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike.

“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant,excipient or carrier with which a compound of the invention isadministered.

“Phosphate” refers to a radical —OP(O)(OR′)(OR″), where R′ and R″ areeach independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined hereinthat may be optionally substituted as defined herein.

“Preventing” or “Prevention” refers to a reduction in risk of acquiringa disease or disorder (i.e., causing at least one of the clinicalsymptoms of the disease not to develop in a patient that may be exposedto or predisposed to the disease but does not yet experience or displaysymptoms of the disease).

“Prodrug” refers to a derivative of a drug molecule that requires atransformation within the body to release the active drug. Prodrugs arefrequently (though not necessarily) pharmacologically inactive untilconverted to the parent drug.

“Promoiety” refers to a form of protecting group that when used to maska functional group within a drug molecule converts the drug into aprodrug. Typically, the promoiety will be attached to the drug viabond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.

“Protecting group” refers to a group of atoms that when attached to areactive group in a molecule masks, reduces or prevents that reactivity.Examples of protecting groups can be found in Green et al., “ProtectiveGroups in Organic Chemistry”, (Wiley, 2^(nd) ed. 1991) and Harrison etal., “Compendium of Synthetic Organic Methods”, vols. 1-8 (John Wileyand Sons, 1971-1996). Representative amino protecting groups include,but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl,benzyloxycarbonyl (“CBZ or Cbz”), tert-butoxycarbonyl (“Boc”),trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“SES”), trityland substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitroveratryloxycarbonyl (“NVOC”)and the like. Representative hydroxyl protecting groups include, but arenot limited to, those where the hydroxyl group is either acylated oralkylated such as benzyl, and trialkylsilyl ethers and allyl ethers.

“Racemate” refers to an equimolar mixture of enantiomers of a chiralmolecule.

“Soft moiety” refers to a moiety that contain hydrolysable bonds thatcan be incorporated into compounds according to the invention includebut not limited are amide, ester, carbonate, phosphate, sulfate, urea,urethane, glycoside, or other bonds that can be cleaved by hydrolases.

“Spacer” refers to a substituent like O, S, alkyl, substituted alkyl,acyl, acylamino, alkoxy, alkylamino, alkylthio, amino, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, arylalkoxy, substitutedarylalkoxy, carboxy, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, and hydroxy.

“Substituted” refers to a group in which one or more hydrogen atoms areeach independently replaced with the same or different substituents(s).Typical substituents include, but are not limited to, —X, —R⁵⁴, —O⁻, ═O,—OR⁵⁴, —SR⁵⁴, —S, ═S, —NR⁵⁴R⁵⁵, —NR⁵⁴, —CX₃, —CF₃, —CN, —OCN, —SCN, —NO,—NO₂, ═N₂, —N₃, —S(O)₂O⁻, —S(O)₂OH, —S(O)₂OR⁵⁴, —OS(O)₂O³¹, —OS(O)₂R⁵⁴,—P(O)(O—)₂, —P(O)(OR¹⁴)(O³¹), —OP(O)(OR⁵⁴)(OR⁵⁵), —C(O)R⁵⁴, —C(S)R⁵⁴,—C(O)OR⁵⁴, —C(O)NR⁵⁴R⁵⁵, —C(O)O⁻, —C(S)OR⁵⁴, —NR⁵⁶C(O)NR⁵⁴R⁵⁵,—NR⁵⁶C(S)NR⁵⁴R⁵⁵, —NR⁵⁷C(NR⁵⁶)NR⁵⁴R⁵⁵, and —C(NR⁵⁶)NR⁵⁴R⁵⁵, where each Xis independently a halogen; each R⁵⁴, R⁵⁵, R⁵⁶ and R⁵⁷ are independentlyhydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, —NR⁵⁸R⁵⁹, —C(O)R⁵⁸ or —S(O)₂R⁵⁸ oroptionally R⁵⁸ and R⁵⁹ together with the atom to which they are bothattached form a cycloheteroalkyl or substituted cycloheteroalkyl ring;and R⁵⁸ and R⁵⁹ are independently hydrogen, alkyl, substituted alkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl.

“Sulfate” refers to a radical —OS(O)(O)OR, where R is hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, as defined herein that may be optionally substituted asdefined herein.

“Thio” means the radical —SH.

“Treating” or “Treatment” of any disease or disorder refers, in oneembodiment, to ameliorating the disease or disorder (i.e., arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof). In another embodiment “treating” or “treatment”refers to ameliorating at least one physical parameter, which may not bediscernible by the patient. In yet another embodiment, “treating” or“treatment” refers to inhibiting the disease or disorder, eitherphysically (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers to delayingthe onset of the disease or disorder.

“Therapeutically effective amount” means the amount of a compound that,when administered to a patient for treating a disease, is sufficient toeffect such treatment for the disease. The “therapeutically effectiveamount” will vary depending on the compound, the disease and is severityand the age, weight, etc., of the patient to be treated, and can bedetermined by one of skill in the art without undue experimentation.

Reference now will be made in detail to preferred embodiments of theinvention. While the invention will be described in conjunction withpreferred embodiments, it will be understood that it is not intended tolimit the invention to those preferred embodiments. To the contrary, itis intended to cover alternatives, modifications, and equivalents as maybe included within the spirit and scope of the invention as defined bythe appended claims

4.2 Compounds of the Invention

The present invention provides cycloalkylmethylamine derivativescomprising compounds of structural Formula (I):

or a pharmaceutically acceptable salt, hydrate or solvate thereof,provided that the compounds of the invention comprise a soft-moietyconjugated directly or via a spacer on one of the substituents R¹, R²,or R³; wherein:

n is 0, 1, 2, 3, 4, or 5;

R¹ and R² are independently selected to be hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,or substituted heteroarylalkyl, or optionally R¹ and R² together withthe atoms to which R¹ and R² are attached, form a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkylring which is optionally fused to an aryl, substituted aryl, heteroaryl,substituted heteroaryl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring;

R³ can be selected to be hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, or substitutedheteroarylalkyl; and

R⁴ can be selected to be hydrogen, alkyl, or substituted alkyl. Thecarbon with the * denotes a carbon capable of being optically active.

The compounds of the invention includes both R and S compounds, andmixture of both R and S compounds. The compounds preferably comprise asoft-moiety where the soft-moiety is a bond cleavable by a hydrolase.Thus, soft-moiety can be an amide bond, an ester bond, a carbonate bond,a phosphate bond, a sulfate bond, an urea bond, and the like. In anotheraspect of the invention, the soft-moiety can comprise a spacer.

In one aspect of the invention, compounds of structural Formula (II) aredescribed,

wherein:

n is 0, 1, 2, 3, 4, or 5;

“SP” refers to a spacer;

X can be O, S, or NR¹⁵ where R¹⁵ can be H, or lower alkyl;

R² can be hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionallyR² and either R⁵ or “SP” (spacer), together with the atoms to which R²and R⁵ or “SP” are attached, form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring which isoptionally fused to an aryl, substituted aryl, heteroaryl, substitutedheteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring;

R³ can be hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, or substituted heteroarylalkyl;

R⁴ can be hydrogen, alkyl, or substituted alkyl;

R⁵ can be hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl; preferablyacyl, acylamino, alkoxy, alkoxycarbonyl, alkoxycarbonylalkoxy,alkoxycarbonylalkylamino, alkylamino, alkylsulfonyl, alkylsulfinyl,alkylthio, amino, arylalkoxy, arylalkoxycarbonylalkoxy,arylalkoxycarbonylalkylamino, aryloxycarbonyl, aryloxycarbonylalkoxy,carbamoyl, carbamate, carboxy, cyano, dialkylamino, ester, halo,heteroalkoxy, hydroxy; or phosphate; heteroaryl, substituted heteroaryl,heteroarylalkyl, or substituted heteroarylalkyl; and

R⁶ can be hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, or substituted heteroarylalkyl.

The carbon with the * denotes a carbon capable of being opticallyactive. The compounds of the invention includes both R and S compounds,and mixture of both R and S compounds. The group R⁶XC(O)-spacer denotesa soft-moiety where the soft-moiety comprises a bond cleavable by ahydrolase. In another aspect of the invention, the soft-moiety can be anamide bond, an ester bond, a carbonate bond, a phosphate bond, a sulfatebond, an urea bond, and the like.

In another aspect of the invention, compounds comprise structuralFormula (III),

wherein:

n is 0, 1, 2, 3, 4, or 5;

“SP” refers to a spacer;

X can be O, S, or NR¹⁵ where R¹⁵ can be H, or lower alkyl;

R³ can be hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, or substituted heteroarylalkyl;

R⁴ can be hydrogen, alkyl, or substituted alkyl;

R⁵ can be hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl; preferablyacyl, acylamino, alkoxy, alkoxycarbonyl, alkoxycarbonylalkoxy,alkoxycarbonylalkylamino, alkylamino, alkylsulfonyl, alkylsulfinyl,alkylthio, amino, arylalkoxy, arylalkoxycarbonylalkoxy,arylalkoxycarbonylalkylamino, aryloxycarbonyl, aryloxycarbonylalkoxy,carbamoyl, carbamate, carboxy, cyano, dialkylamino, ester, halo,heteroalkoxy, hydroxy or phosphate;

R⁷ can be hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl; preferablyacyl, acylamino, alkoxy, alkoxycarbonyl, alkoxycarbonylalkoxy,alkoxycarbonylalkylamino, alkylamino, alkylsulfonyl, alkylsulfinyl,alkylthio, amino, arylalkoxy, arylalkoxycarbonylalkoxy,arylalkoxycarbonylalkylamino, aryloxycarbonyl, aryloxycarbonylalkoxy,carbamoyl, carbamate, carboxy, cyano, dialkylamino, ester, halo,heteroalkoxy, hydroxy or phosphate; or optionally R⁵ and R⁷ togetherwith the atoms to which R⁵ and R⁷ are attached, form a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkylring which is optionally fused to an aryl, substituted aryl, heteroaryl,substituted heteroaryl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring; and

R⁶ can be hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, or substituted heteroarylalkyl.

The carbon with the * denotes a carbon capable of being opticallyactive. The compounds of the invention includes both R and S compounds,and mixture of both R and S compounds.

In yet another aspect, the invention provides compounds of structuralFormula (IV),

wherein:

n can be 0, 1, 2, 3, 4, or 5;

“SP” refers to a spacer;

X can be O, S, or NR¹⁵ where R¹⁵ can be H, or lower alkyl;

R² can be hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionallyR² and either R⁵ or R⁷ together with the atoms to which R² and R⁵ or R⁷,form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring which is optionally fused to an aryl,substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkylring;

R⁴ can be hydrogen, alkyl, or substituted alkyl;

R⁵ can be hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl; acyl,acylamino, alkoxy, alkoxycarbonyl, alkoxycarbonylalkoxy,alkoxycarbonylalkylamino, alkylamino, alkylsulfonyl, alkylsulfinyl,alkylthio, amino, arylalkoxy, arylalkoxycarbonylalkoxy,arylalkoxycarbonylalkylamino, aryloxycarbonyl, aryloxycarbonylalkoxy,carbamoyl, carbamate, carboxy, cyano, dialkylamino, ester, halo,heteroalkoxy, hydroxy, or phosphate; or optionally R⁵ and R⁷ togetherwith the atoms to which R⁵ and R⁷, form a cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring whichis optionally fused to an aryl, substituted aryl, heteroaryl,substituted heteroaryl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring;

R⁷ can be hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl; preferablyacyl, acylamino, alkoxy, alkoxycarbonyl, alkoxycarbonylalkoxy,alkoxycarbonylalkylamino, alkylamino, alkylsulfonyl, alkylsulfinyl,alkylthio, amino, arylalkoxy, arylalkoxycarbonylalkoxy,arylalkoxycarbonylalkylamino, aryloxycarbonyl, aryloxycarbonylalkoxy,carbamoyl, carbamate, carboxy, cyano, dialkylamino, ester, halo,heteroalkoxy, hydroxy or phosphate; or optionally R⁵ and R⁷ togetherwith the atoms to which R⁵ and R⁷ are attached, form a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkylring which is optionally fused to an aryl, substituted aryl, heteroaryl,substituted heteroaryl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring; and

R⁶ can be hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, or substituted heteroarylalkyl.

The carbon with the * denotes a carbon capable of being opticallyactive. The compounds of the invention includes both R and S compounds,and mixture of both R and S compounds.

The compounds of this invention described herein can have one or more ofthe following characteristics or properties:

-   -   1. Compounds of the invention can have dopamine, norepinephrine        and serotonin reuptake inhibitory properties;    -   2. Compounds of the invention can have dopamine transporter        (DAT), norepinephrine transporter (NET) and serotonin        transporter (SERT) inhibitory properties;    -   3. Compounds according to the invention contain at least one        hydrolysable bond that can be cleaved non-oxidatively by        hydrolytic enzymes;    -   4. The primary metabolites of compounds of this invention        results from the non-oxidative metabolism of the compounds;    -   5. The primary metabolites, regardless of the        electrophysiological properties of the parent drug, has, or        have, negligible inhibitory activity at the IKr (HERG) channel        at the normal therapeutic concentration of the parent drug in        plasma (e.g. the concentration of the metabolite must be at        least five times higher than the normal therapeutic        concentration of the parent compound before activity at the IKr        channel is observed);    -   6. Compounds of the invention, as well as the metabolites        thereof, do not cause metabolic drug-drug interaction (DDI) when        co-administered with other drugs;    -   7. Compounds of the invention, as well as metabolites thereof,        do not elevate liver function test (LFT) values when        administered alone;    -   8. Oral bioavailability of the compounds is consistent with oral        administration using standard pharmacological oral formulations;        however, the compounds, and compositions thereof, can also be        administered using any delivery system that produces constant        and controllable blood levels overt time.

In some embodiments, the subject invention provides compounds having anytwo or more of the above identified characteristics or properties. Otherembodiments provide for compounds having at least any three or more ofthe above identified properties or characteristics. In anotherembodiment, the compounds, and compositions thereof, have anycombination of four to eight of the above identified characteristics orproperties. In a preferred embodiment the compounds of the inventionhave all eight characteristics or properties.

Preferably, the primary metabolites of the inventive compounds,regardless of the electrophysiological properties of the parent drug,have negligible inhibitory activity at the IKr (HERG) channel at normaltherapeutic concentrations of the drug in plasma. In other words, theconcentration of the metabolite preferably is at least five times higherthan the normal therapeutic concentration of the parent compound beforeactivity at the IKr channel is observed. Preferably, the concentrationof the metabolite is at least ten times higher than the normaltherapeutic concentration of the parent compound before activity at theIKr channel is observed.

Compounds according to the invention are primarily metabolized byendogenous hydrolytic enzymes via hydrolysable bonds engineered intotheir structures. The primary metabolites resulting from this metabolicpathway are water soluble and do not have, or show a reduced incidenceof, DDI when administered with other medications (drugs). Non-limitingexamples of hydrolysable bonds that can be incorporated into compoundsaccording to the invention include amide, ester, carbonate, phosphate,sulfate, urea, urethane, glycoside, or other bonds that can be cleavedby hydrolases.

Additional modifications of the compounds disclosed herein can readilybe made by those skilled in the art. Thus, analogs and salts of theexemplified compounds are within the scope of the subject invention.With knowledge of the compounds of the subject invention skilledchemists can use known procedures to synthesize these compounds fromavailable substrates. As used in this application, the term “analogs”refers to compounds which are substantially the same as another compoundbut which may have been modified by, for example, adding additional sidegroups. The term “analogs” as used in this application also may refer tocompounds which are substantially the same as another compound but whichhave atomic or molecular substitution at certain locations in thecompound.

The subject invention further pertains to enantiomerically isolatedcompounds, and compositions comprising the compounds. The isolatedenantiomeric forms of the compounds of the invention are substantiallyfree from one another (i.e., in enantiomeric excess). In other words,the “R” forms of the compounds are substantially free from the “S” formsof the compounds and are, thus, in enantiomeric excess of the “S” forms.Conversely, “S” forms of the compounds are substantially free of “R”forms of the compounds and are, thus, in enantiomeric excess of the “R”forms. In one embodiment of the invention, the isolated enantiomericcompounds are at least about in 80% enantiomeric excess. In a preferredembodiment, the compounds are in at least about 90% enantiomeric excess.In a more preferred embodiment, the compounds are in at least about 95%enantiomeric excess. In an even more preferred embodiment, the compoundsare in at least about 97% enantiomeric excess. In a most preferredembodiment, the compounds are in at least 99% or greater than 99%enantiomeric excess.

4.3 Synthesis of the Compounds of the Invention

The compounds of the invention can be obtained via the synthetic methodsillustrated in Schemes 1-11. Those of skill in the art will appreciatethat a preferred synthetic route to the compounds of the invention willconsist of attaching or incorporating soft-moieties tocycloalkylmethylamines of Formulae (I), (II), (III) and (IV). Severalmethods have been described in the art for the synthesis ofcycloalkylmethylamine analogs (see, e.g. Mattson, R. J. et al. U.S. Pat.No. 5,596,019; Lulla, A. et al., International Application PublicationNo. WO 2004/096202; Senanayake, C. H. et al., International ApplicationPublication No. WO 02/083631; Vyas, S. K. et al., InternationalApplication Publication No. WO 02/36540; Jerussi, T. P. et al.,International Application Publication No. WO 02/060424; Jeffery, J. E.et al., J. Chem. Soc. Perkin Trans 1, 1996, 2583-2589.). Other methodsare known in the art for synthesizing cycloalkylmethylamines, which arereadily accessible to the skilled artisan. The soft-moieties attached tospacers thereof are commercially available or can be prepared byestablished procedures (See e.g., Green et al., “Protective Groups inOrganic Synthesis,” (Wiley™, 4^(rd) ed., 2006); Harrison et al“Compendium of Synthetic Organic Methods,” vols. 1-8 (John Wiley andSons, 1971-1996); “Beilstein Handbook of Organic Chemistry, Frankfurt,Germany; Feiser et al, “Reagents for Organic Synthesis,” Volumes 1-45,Karger, 1991; March, Advanced Organic Chemistry,” Wiley Interscience,4^(th) ed., 1992; Larock “Comprehensive Organic Transformations,”Wiley-VCH Publishers, 2^(nd) ed., 1999; Paquette, “Encyclopedia ofReagents for Organic Synthesis,” John Wiley and Sons, 1^(st) ed., 1995).

Accordingly, starting materials useful for preparing compounds of theinvention and intermediates thereof are commercially available or can beprepared by well-known synthetic methods. Other methods for thesynthesis of cycloalkylmethylamines described herein are eitherdescribed in the art or will be readily apparent to the skilled artisanin view of the references provided above and may be used to synthesizethe compounds of the invention. Accordingly, the methods presented inthe Schemes herein are illustrative rather than comprehensive.

In one general method for synthesis of compounds of Formulae (I)-(IV) isdescribed in Scheme 1. An appropriate substituted phenylacetonitrile (1)is reacted with dibromoalkane (2) in appropriate solvent (e.g., ether,THF, dioxane, DMF, DMSO) at a temperature between 10 and 100° C.,preferably between 20 and 75° C. in the presence of a base (e.g., NaH,KOH) to give cycloalkylnitrile (3). The cycloalkylnitrile compounds areused to synthesize compounds (6) using a tandem Grignard-reductionmethod. The typical procedure involves the reaction of compound (3) withan appropriate Grignard reagent (R¹¹MgBr) in presence of an appropriatesolvent (e.g., ether, THF, toluene) at a temperature between 0 and 90°C. for 1 to 24 hours. Then the resulting adduct is subjected toreduction without any workup procedures using reducing agent like sodiumborohydride according to a standard or an established procedure (see,Jeffery et al., J. Chem. Soc., Perkin Trans. 1, 1996, 2583-2589) toproduce the corresponding cycloalkylmethylamine (6). The amino group incompounds 6 can be alkylated directly using appropriate alkyl halides orsequentially by reductive alkylation methods using standard procedureswell known in the art to provide compounds (10). In one method, anappropriate carboxylic acid can be coupled to a compound (6) usingstandard peptide coupling reagents like DCC or DIC followed by reducingthe corresponding amide (9) with using a reducing agent like boraneunder standard reduction conditions well known in the art. Compound (10)can be further alkylated using appropriate alkyl halides in the presenceof a suitable base (e.g., TEA, DIEA, pyridine, cesium carbonate) understandard conditions.

In another general method for synthesis of compounds of Formulae(I)-(IV) can be prepared from cycloalkylmethylamines (6) as described inScheme 2. Compound (6) can be reacted with an appropriate spacercarrying a soft-moiety (13) under standard alkylating conditions wellknown in the art to provide the corresponding cycloalkylmethylamine(14).

Another general method for synthesis of compounds of Formulae (I)-(IV)begins with an appropriate cycloalkylnitrile (3) in a stepwise fashionas illustrated in Scheme 3. Here reaction of compound (3) with anappropriate Grignard reagent (15) carrying a masked functional grouplike protected hydroxyl moiety followed by in situ reduction of thecorresponding imine (16) using sodium borohydride as described above forthe synthesis of compound (6) in Scheme 1 affords the correspondingcycloalkylmethylamine (17). A number of Grignard reagents having maskedfunctional or pro-functional groups can be used in this reaction andmost preferred functional groups is hydroxy (OH). Several Grignardreagents carrying masked functional group are commercially available andthey can also be prepared by methods well known to the skilled artisan.Then, protection of amino moiety with a global protecting group,benzyloxycarbonyl (Cbz) group by treating with a commercially availablereagent benzylchloroformate followed by deprotection oftert-butyldimethylsilane (TBS) protecting group under standardconditions affords the corresponding N-benzyloxycarbonyl (N-Cbz)protected cycloalkylmethylamine (18). Compound (18) upon subjected tooxidation using pyridinium chlorochromate (PCC) or any other standardoxidizing agents to provide carboxylic acid which after reacting with anappropriate alcohol (R¹⁴OH) or amine (R¹⁴NH₂) affords the correspondingcarboxylic acid ester or amide derivative of N-Cbz protectedcycloalkylmethylamine (22). Deprotection of Cbz protecting group withpalladium on activated carbon in hydrogen atmosphere affords compound(23). The amino moiety of cycloalkylmethylamine (23) can be furtherderivatized using alkyl halides (R¹³L) under standard reactionconditions well known in the art of as described for the compounds (12)and (14) in Scheme 1 and 2, respectively.

Another general method for synthesis of compounds of Formulae (I)-(IV)begins with an appropriate cycloalkylnitrile (3) in a stepwise fashionas illustrated in Scheme 4. Here reaction of compound (3) with anappropriate Grignard reagent (25) carrying a masked aldehyde groupfollowed by in situ reduction of the corresponding imine (26) usingsodium borohydride as described above for the synthesis of compounds (6)and (17) in Scheme 1 and 3, respectively, affords the correspondingcycloalkylmethylamine (27). A number of Grignard reagents having maskedaldehyde functional group can be used in this reaction and mostpreferred ones are 5- and 6-member cyclic acetals. Several Grignardreagents carrying masked functional group are commercially available andthey can also be prepared by methods well known to the skilled artisan.Then, protection of amino moiety in with a global protecting group,benzyloxycarbonyl group by treating with a commercially availablereagent benzylchloroformate followed by acid catalyzed cleavage ofcyclic acetal protecting group under standard conditions affords thecorresponding N-Cbz protected cycloalkylmethylamine (29). Compound (29)upon subjected to oxidation using pyridinium chlorochromate (PCC) or anyother standard oxidizing agents to provide carboxylic acid (30) whichafter reacting with an appropriate alcohol (R¹⁴OH) or amine (R¹⁴NH₂)affords the corresponding carboxylic acid ester or amide derivative ofN-Cbz protected cycloalkylmethylamine (22), respectively, which can befurther converted in to compounds 23 and 24 as illustrated in Scheme 3.

Another general method for synthesis of compounds of Formulae (I)-(IV)is described in Scheme 5, where cycloalkylmethylamines carryingappropriate substituents having esterase cleavable group such ascarboxylic acid esters and amides are synthesized. In a typical example,a reaction of phenylacetonitrile (3) and appropriate halide (31)carrying protected hydroxyl group in the presence of a base (e.g.,potassium carbonate, cesium carbonate) in a solvent (e.g., acetone, DMF)at a temperature between ambient and 125° C., preferably between 25° C.and 95° C. provides the expected compound (32). Thecycloalkylmethylamines (37) and (38) carrying a soft-moiety can beprepared from compound (32) in a stepwise fashion as illustrated inScheme 4 and also by using the methods described in Schemes 1 to 3.

Another general method for synthesis of compounds of Formulae (I)-(IV)is described in Scheme 6, where cycloalkylmethylamines carryingappropriate substituents having terminal ester or amide groups aresynthesized. In a typical example, a reaction of phenylacetonitrile (3,R¹⁰═OH) carrying a phenolic OH moiety is protected with an appropriateprotecting group like tert-butyldimethylsilyl (TBS) group under standardreaction conditions to give the compound 39. The compound 39 is reactedwith appropriate Grignard reagent 4 (R¹¹MgBr) as described for thesynthesis of compound 6 in Scheme 1 to afford compound 41. Thecycloalkylmethylamines (45) and (46) carrying a soft-moiety can beprepared from compound (41) in a stepwise fashion as illustrated inScheme 5 and also by using the methods described in Schemes 1 to 4.

In one method selected cyclobutanealkylamines comprising Formula (IV)were prepared as described in Scheme 7. An appropriate substitutedphenylacetonitrile (47) was reacted with 1,3-dibromopropane (48) inanhydrous tetrahydrofuran at ice-bath temperature to room temperature togive the corresponding cycloalkylnitrile (49). The cycloalkylnitrilecompounds (49) were used for synthesizing compounds (52) using a tandemGrignard-reduction method as described in the general method forsynthesis of cycloalkylmethylamines and illustrated in Scheme 1. Theamino group in compounds 52 was alkylated directly using appropriatealkyl halides carrying a terminal ester moiety using cesium carbonate ina polar aprotic solvent DMF at room temperature to 60° C. to afford thecorresponding N-alkylated compounds 54. The presence oftetrabutylammonium iodide in the reaction mixture was found to increasethe yield of 54 and also accelerate the completion of the reaction to agreat extent.

Other methods for synthesis of cycloalkylamines comprising Formula (I)and (IV) were prepared as described in Scheme 8. The cycloalkylaminecarrying a terminal carboxylic acid ester moiety 54a was prepared byreacting ethyl glyoxylate under reductive alkylation conditions usingsodium triacetoxyborohydride as reducing agent. The cycloalkylaminecarrying a terminal carboxylic ester moiety 54e was prepared from thecycloalkylamine 52a in three steps as described in Scheme 8. Thecompound 57 was prepared by reductive alkylation of 52a withbenzaldehyde under standard conditions in good yield which was furtheralkylated with 5-bromovalerate using a strong base n-butyllithium(n-BuLi) to give the corresponding trialkyl compound 58. The benzylgroup in compound 58 was cleaved off under standard hydrogenolysisconditions using palladium on activated carbon in presence of hydrogenatmosphere and few drops of hydrochloric acid in ethyl acetate assolvent to give the corresponding amine 54e.

The synthesis of building blocks 47 is illustrated in Scheme 9.4-Chlorophenylacetonitrile (47a) is commercially available and waspurchased from Aldrich. The compounds 47b-d were prepared from4-hydroxyphenylacetonitrile (59). The compound 47b was prepared byalkylating 59 with benzyl bromide using potassium carbonate as base inDMF as solvent in good yield. Similarly, the compound 47c wassynthesized by alkylating 59 with 4-methoxybenzaldehyde in good yield.The reaction of tert-butyldimethylsilyl chloride (TBSCl) with 59 inpresence of base imidazole and 10 mol % of N,N-dimethylaminopyridine(DMAP) in dichloromethane afforded the corresponding 47d in good yield.

In another method cyclobutanealkylamines comprising Formula (I) and (IV)were prepared as described in Scheme 10.4-Chlorophenylcyclobutaneacetonitrile (49a) was reacted withcommercially available Grignard reagent having masked aldehydefunctional group 63 as illustrated in Scheme 4 to give the correspondingcyclobutanealkylamines carrying masked aldehyde functional group 65. Thecompounds 65 can be further derivatized to give cyclobutanealkylaminescarrying esters and amides as illustrated in Scheme 4.

In another method selected examples of cycloalkylamines carryingterminal esters or amides comprising general Formulae (I) and (II) wereprepared as described in Scheme 11. The amine moiety incyclobutanealkylamine 52d was protected with tert-butyloxycarbonyl (BOC)group to give N—BOC protected amine 66. Then, the TBS protecting groupon 66 was cleaved off under neutral conditions using aqueous DMSO at50-90° C. to give 67. The N—BOC protected phenol 67 was alkylated withethyl bromoacetate under standard alkylating conditions using cesiumcarbonate as base in anhydrous DMF to afford the compound 69 which aftertreatment with trifluoroacetic acid in DCM gave the correspondingcyclobutanealkylamine carrying terminal carboxylic acid estersubstituents 70.

4.4 Therapeutic Uses of Compounds of Structural Formulae

The present invention provides methods of treating and preventingobesity and associated co-morbid conditions. The term “co-morbidconditions associated with obesity” used in this document means medicalconditions known to those skilled in the art to be associated withobesity. The term includes but not limited to the following: diabetesincluding non-insulin dependent diabetes mellitious, impaired glucosetolerance, hypertension, coronary thrombosis, stroke, depression,anxiety, psychoses (for example schizophrenia), tardive dyskinesia, drugaddiction, drug abuse, cognitive disorders, Alzheimer's disease,cerebral ischaemia, obsessive-compulsive behavior, panic attacks, socialphobias, eating disorders such as bulimia, anorexia, snacking and bingeeating, lipid syndromes, hyperglycemia, hyperlipidemia, and stress inmammals particularly humans.

In addition, the compounds, compositions, and methods of the presentinvention can be used in the treatment or prevention of metabolicdiseases and conditions arising therefrom, or for example non exerciseactivity thermogenesis and increased metabolic rate, sexual dysfunction,sleep apnoea, premenstrual syndrome, urinary incontinence includingstress incontinence, hyperactivity disorders, hiatial hernia, and refluxesophagitis, pain, especially neuropathic pain, weight gain associatedwith drug treatment, chronic fatigue syndrome, osteoarthritis and gout,cancers associated with weight gain, menstrual dysfunction, gallstones,orthostatic hypotension and pulmonary hypertension.

The compounds, compositions, and methods of the present invention can beuseful in preventing cardiovascular disease, and in reducing plateletadhesiveness, in aiding weight loss after pregnancy, reducing thecraving to smoke and in aiding weight loss after smoking cessation. Thepresent invention can also be useful in lowering uric acid levels andlipid levels in mammals particularly humans.

In accordance with the invention, a compound and/or a compositioncontaining a compound of structural Formulae (I), (II), (III) or (IV) isadministered to a patient, preferably a human, suffering from obesityand associated with co-morbid diseases and/or disorders. Further, incertain embodiments, the compounds and/or compositions of the inventionare administered to a patient, preferably a human, as a preventivemeasure against various diseases or disorders. Thus, the compoundsand/or compositions containing compound(s) of structural Formulae (I),(II), (III) or (IV) may be administered as a preventive measure to apatient having a predisposition for obesity and associated co-morbiddiseases and/or disorders (see, Montana, J. G. International ApplicationPublication No. WO 2004/058237; Lulla, A. et al., InternationalApplication Publication No. WO 2004/096202; Jerussi, T. P. et al.,International Application Publication No. WO 02/060424; Senanayake, C.H. et al., International Application Publication No. WO 01/51453; Heal,D. J. International Application Publication No. WO 01/00205; Birch, A.M. et al., International Application Publication No. WO 01/00187;Mueller, P. International Application Publication No. WO 00/32178;Bailey, C. International Application Publication No. WO 98/11884; Kelly,P. International Application Publication No. WO 98/13034).

Thus, those of skill in the art may readily assay and use the compoundsand/or compositions containing compound(s) of structural Formulae (I),(II), (III) or (IV) to treat obesity and associated co-morbid diseasesand/or disorders.

4.5 Therapeutic/Prophylactic Administration

The compounds, and/or compositions containing compounds(s), ofstructural Formulae (I), (II), (III) or (IV) can be advantageously usedin human medicine. As previously described in Section 4.4 above,compounds and compositions containing compound(s) of structural Formulae(I), (II), (III) or (IV) are useful for the treatment or prevention ofobesity and associated co-morbid diseases and/or disorders.

When used to treat or prevent the above disease or disorders compoundsand/or compositions of the invention can be administered or appliedsingly, in combination with other agents. The compounds and/orcompositions of the invention can also be administered or appliedsingly, in combination with other pharmaceutically active agents,including other compounds and/or compositions of the invention.

The current invention provides methods of treatment and prophylaxis byadministration to a patient of a therapeutically effective amount of acomposition and/or compound of the invention. The patient may be ananimal, is more preferably a mammal, and most preferably a human.

The present compounds and/or compositions of the invention, whichcomprise one or more compounds and/or compositions of the invention arepreferably administered orally. The compounds and/or compositions of theinvention may also be administered by any other convenient route, forexample, by infusion or bolus injection, by absorption throughepithelial or mucocutaneous linings (e.g., oral mucosa, rectal andintestinal mucosa, etc.). Administration can be systemic or local.Various delivery systems are known, (e.g., encapsulation in liposomes,microparticles, microcapsules, capsules, etc.) that can be used toadminister a compound and/or composition of the invention. Methods ofadministration include, but are not limited to, intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intranasal, intracerebral, intravabinal,transdermal, rectally, by inhalation, or topically, particularly to theears, nose, eyes or skin.

In particularly, preferred embodiments, the compounds and/orcompositions of the invention can be delivered via sustained releasesystems, preferably oral sustained release systems. In one embodiment, apump may be used (see, Langer, supra; Sefton, 1987, CRC Crit. RefBiomed. Eng. 14:201; Saudek et al., 1989, N. Engl. J. Med. 321:574).

In another embodiment, polymeric materials can be used (see “MedicalApplications of Controlled Release,” Langer and Wise (eds.), Wiley, NewYork (1984); Ranger and Peppas, 1983, J. Macromol. Sci. Rev. MacromolChem. 23:61; see also Levy et al., 1985, Science 228:190; During et al.,1989, Ann. Neurol. 25:351; Howard et al, 1989, J. Neurosurg. 71:105). Ina preferred embodiment, polymeric materials are used for oral sustainedrelease delivery. Preferred polymers include sodiumcarboxymethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose and hydroxyethylcellulose (most preferred,hydroxypropylmethylcellulose). Other preferred cellulose ethers havebeen described in the art (Bamba et al., Int. J. Pharm., 1979, 2, 307).

In another embodiment, enteric-coated preparations can be used for oralsustained release administration. Preferred coating materials includepolymers with a pH-dependent solubility (i.e., pH-controlled release),polymers with a slow or pH-dependent rate of swelling, dissolution orerosion (i.e., time controlled release), polymers that are degraded byenzymes (i.e., enzyme controlled release) and polymers that form firmlayers that are destroyed by an increase in pressure (i.e.,pressure-controlled release).

In still another embodiment, osmotic delivery systems are used for oralsustained release administration (Verma et al., Drug Dev. Ind. Pharm.,2000, 26:695-708). In a preferred embodiment, OROS® osmotic deliverysystems sold by Alza Corporation of Mountain View, Calif. are used fororal sustained release delivery devices (See for example, Theeuwes etal., U.S. Pat. No. 3,845,770; and Theeuwes et al, U.S. Pat. No.3,916,899).

In yet another embodiment, a controlled-release system can be placed inproximity of the target of the compounds and/or composition of theinvention, thus requiring only a fraction of the systemic dose (See,e.g., Goodson, in “Medical Applications of Controlled Release,” supra,vol. 2, pp. 115-138 (1984)). Other controlled-release systems discussedin Langer, 1990, Science 249:1527-1533 may also be used.

The compounds, and/or compositions containing compound(s) of structuralFormulae (I), (II), (III) or (IV) of the invention may be cleaved eitherchemically and/or enzymatically. One or more enzymes present in thestomach, intestinal lumen, intestinal tissue, blood, liver, brain or anyother suitable tissue of a mammal may enzymatically cleave the compoundsand/or compositions of the invention.

4.6 Compositions of the Invention

The present composition contain a therapeutically effective amount ofone or more compounds of the invention, preferably in purified form,together with a suitable amount of a pharmaceutically acceptablevehicle, which so as to provide the form for proper administration to apatient. When administered to a patient, the compounds of the inventionand pharmaceutically acceptable vehicles are preferably sterile. Wateris preferred vehicle when the compound of the invention is administeredintravenously. Saline solutions and aqueous dextrose and glycerolsolutions can also be employed as liquid vehicles, particularly forinjectable solutions. Suitable pharmaceutical vehicles also includeexcipients such as starch, glucose, lactose, sucrose, gelatin, malt,rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate,talc, sodium chloride, dried skim milk, glycerol, propylene, glycol,water, ethanol and the like. The present agents, or pH buffering agents.In addition, auxiliary, stabilizing, thickening, lubricating andcoloring agents may be used.

Pharmaceutical compositions comprising a compound of the invention maybe manufactured by means of conventional mixing, dissolving,granulating, dragee-making levigating, and emulsifying, encapsulating,entrapping or lyophilizing process. Pharmaceutical compositions may beformulated in conventional manner using one or more physiologicallyacceptable carriers, diluents, excipients or auxiliaries, whichfacilitate processing of compounds of the invention into preparationswhich can be used pharmaceutically. Proper formulation is dependent uponthe route of administration chosen.

The present compositions can take the form of solutions, suspensions,emulsion, tablets, pills, pellets, and capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foruse. In one embodiment, the pharmaceutically acceptable vehicle is acapsule (see e.g., Grosswald et al., U.S. Pat. No. 5,698,155). Otherexamples of suitable pharmaceutical vehicles have been described in theart (see Remington's Pharmaceutical Sciences, Philadelphia College ofPharmacy and Science, 17^(th) Edition, 1985). Preferred compositions ofthe invention are formulated for oral delivery, particularly for oralsustained release administration.

Compositions for oral delivery may be in the form of tablets, lozenges,aqueous or oily suspensions, granules, powders, emulsions, capsules,syrups or elixirs, for example. Orally administered compositions maycontain one or more optionally agents, for example, sweetening agentssuch as fructose, aspartame or saccharin; flavoring agents such aspeppermint, oil of wintergreen, or cherry coloring agents and preservingagents to provide a pharmaceutically palatable preparation. Moreover,where in tablet or pill form, the compositions may be coated to delaydisintegration and absorption in the gastrointestinal tract, therebyproviding a sustained action over an extended period of time.Selectively permeable membranes surrounding an osmotically activedriving compound are also suitable for orally administered compounds ofthe invention. In these later platforms, fluid from the environmentsurrounding the capsule is imbibed by the driving compound, which swellsto displace the agent or agent composition through an aperture. Thesedelivery platforms can provide an essentially zero order deliveryprofile as opposed to the spiked profiles of immediate releaseformulations. A time delay material such as glycerol monostearate orglycerol stearate may also be used. Oral compositions can includestandard vehicles such as mannitol, lactose, starch, magnesium stearate,sodium saccharine, cellulose, magnesium carbonate, etc. Such vehiclesare preferably of pharmaceutical grade.

For oral liquid preparations such as, for example, suspensions, elixirsand solutions, suitable carriers, excipients or diluents include water,saline, alkyleneglycols (e.g., propylene glycol), polyalkylene glycols(e.g., polyethylene glycol) oils, alcohols, slightly acidic buffersbetween pH 4 and pH 6 (e.g., acetate, citrate, ascorbate at betweenabout mM to about 50 mM) etc. Additionally, flavoring agents,preservatives, coloring agents, bile salts, acylcamitines and the likemay be added.

Compositions for administration via other routes may also becontemplated. For buccal administration, the compositions may take theform of tablets, lozenzes, etc. formulated in conventional manner.Liquid drug formulations suitable for use with nebulizers and liquidspray devices and EHD aerosol devices will typically include a compoundof the invention with a pharmaceutically acceptable vehicle. Preferably,the pharmaceutically acceptable vehicle is a liquid such as alcohol,water, polyethylene glycol or a perfluorocarbon. Optionally, anothermaterial may be added to alter the aerosol properties of the solution orsuspension of compounds of the invention. Preferably, this material isliquid such as alcohol, glycol, polyglycol or fatty acid. Other methodsof formulating liquid drug solutions or suspension suitable for use inaerosol devices are known to those of skill in the art (see, e.g.,Biesalski, U.S. Pat. No. 5,112,598; Biesalski, U.S. Pat. No. 5,556,611).A compound of the invention may also be formulated in rectal or vaginalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa, butter or otherglycerides. In addition to the formulations described previously, acompound of the invention may also be formulated as depot preparation.Such long acting formulations may be administered by implantation (forexample, subcutaneously or intramuscularly) or by intramuscularinjection. Thus, for example, a compound of the invention may beformulated with suitable polymeric or hydrophobic materials (forexample, as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives, for example, as a sparingly solublesalt.

When a compound of the invention is acidic, it may be included in any ofthe above-described formulations as the free acid, a pharmaceuticallyacceptable salt, a solvate or hydrate. Pharmaceutically acceptable saltssubstantially retain the activity of the free acid, may be prepared byreaction with bases and tend to be more soluble in aqueous and otherprotic solvents than the corresponding free acid form.

4.7 Methods of Use and Doses

A compound of the invention, or compositions thereof, will generally beused in an amount effective to achieve the intended purpose. For use totreat or prevent obesity and associated co-morbid diseases and/ordisorders the compounds of Formulae (I), (II), (III) or (IV) andcompositions containing a compound of Formulae (I), (II), (III) or (IV)are administered or applied in a therapeutically effective amount.

The amount of a compound of the invention that will be effective in thetreatment of a particular disorder or condition disclosed herein willdepend on the nature of the disorder or condition, and can be determinedby standard clinical techniques known in the art as previouslydescribed. In addition, in vitro or in vivo assays may optionally beemployed to help identify optimal dosage ranges. The amount of acompound of the invention administered will, of course, is dependent on,among other factors, the subject being treated, and the weight of thesubject, the severity of the affliction, the manner of administrationand the judgment of the prescribing physician. For example, the dosagemay be delivered in a pharmaceutical composition by a singleadministration, by multiple applications or controlled release. In apreferred embodiment, the compounds of the invention are delivered byoral sustained release administration. Preferably, in this embodiment,the compounds of the invention are administered twice per day (morepreferably, once per day). Dosing may be repeated intermittently, may beprovided alone or in combination with other drugs and may continue aslong as required for effective treatment of the disease state ordisorder.

The compounds and/or compositions containing compound(s), of structuralFormulae (I)-(IV) for the pharmacological treatment of obesity andrelated co-morbid indications may be administered in the range 0.1 mg to500 mg preferably 1 mg to 100 mg per day given in one or more doses andmore preferably 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 35 mg or 50 mg per dayand most preferably 25 mg.

The compounds of the invention are preferably assayed in vitro and invivo, for the desired therapeutic or prophylactic activity, prior to usein humans. The compounds of the invention may also be demonstrated to beeffective and safe using animal model systems.

Preferably, the therapeutically effective dose of a compound of theinvention described herein will provide therapeutic benefit withoutcausing substantial toxicity. Toxicity of compounds of the invention maybe determined using standard pharmaceutical procedures and may bereadily ascertained by the skilled artisan. The dose ratio between toxicand therapeutic effect is the therapeutic index. A compound of theinvention will preferably exhibit particularly high therapeutic indicesin treating disease and disorders. The dosage of a compound of theinventions described herein will preferably be within a range ofcirculating concentrations that include an effective dose with little orno toxicity.

4.8 Combination Therapy

In certain embodiments of the present invention, the compounds of theinvention can be used in combination therapy with at least one othertherapeutic agent. The compound of the invention and the therapeuticagent can act additively or, more preferably, synergistically. In apreferred embodiment, composition comprising a compound of the inventionis administered concurrently with the administration of anothertherapeutic agent, which can be part of the same composition. In anotherembodiment, a composition comprising a compound of the invention isadministered prior or subsequent to administration of anothertherapeutic agent.

5. EXAMPLES

The invention is further defined by reference to the following examples,which describe in detail preparation of compounds and compositions ofthe invention and assays for using compounds and compositions of theinvention. It will be apparent to those skilled in the art that manymodifications, both to materials and methods, may be practiced withoutdeparting from the scope of the invention.

In the examples below, the following abbreviations have the followingmeanings. If an abbreviation is not defined, it has its generallyaccepted meaning.

AcOH=Acetic acid

Atm=Atmosphere

Cbz=carbobenzyloxy

DCM=dichloromethane

DMAP=4-N,N-dimethylaminopyridine

DMF=N,N-dimethylformamide

DMSO=dimethylsulfoxide

g=gram

h=hours

L=liter

LC/MS=liquid chromatography/mass spectroscopy

M=molar

mL=milliliter

mmol=millimols

TBS=tert-butyldimethylsilyl

TEA=triethylamine

THF=tetrahydrofuran

TFA=trifluoroacetic acid

Example 1 General Procedure for Synthesis of 49a-d (Scheme 7)

The phenylcyclobutanenitriles 49a-d were prepared according to theprotocol reported by Butler and Polatz (J. Org. Chem. 1971, 36, 1308).To a stirred suspension of sodium hydride (NaH) (0.1 mole, 2.4 g) in 25mL of anhydrous tetrahydrofuran (THF) under nitrogen atmosphere atice-bath temperature was dropwise added a solution of 1,3-dibromopropane(11.10 g, 0.055 mole) and appropriate benzylnitrile 47a-d (0.05 mole) in50 mL of THF. The resulting mixture was slowly warmed to roomtemperature and continued stirring overnight (12 hours) at roomtemperature. The progress of the reaction was monitored by thin layerchromatography (TLC). The reaction was poured onto crushed ice (200 g)and then, extracted with ethyl acetate (100 mL×3). The combined extractwas washed with water (100 mL×2), dried over magnesium sulfate (MgSO₄)and evaporated under reduced pressure to give the correspondingphenylcyclobutanenitriles 49a-d which were purified by silica gel columnchromatography technique using 0-50% gradient of ethyl acetate andhexane in good yields. The pure products 49a-d gave satisfactory ¹H NMRand/or Mass spectral data.

1-(4-Chlorophenyl)cyclobutanecarbonitrile (49a)

Colorless oil (7.60 g, 79%). It was also purchased from commercialsource, Aldrich. ¹H NMR data of the synthesized 49a is in agreement withthe reported values and also the data matches with the values obtainedfrom the commercial compound.

1-[(4-tert-butyldimethylsilyloxy)phenyl]cyclobutanecarbonitrile (49b)

Colorless oil (10.30 g, 72%). ¹H NMR (400 MHz, CDCl₃): δ 0.01 (6H, s);0.78 (9H, s); 1.86 (2H, m); 2.37 (2H, m); 2.59 (2H, m); 6.50 (2H, d,J=7.5 Hz); 7.05 (2H, d, J=7.5 Hz). MS (ESI): m/z=575.40 (M×2+H⁺).

1-[(4-Benzyloxy)phenyl]cyclobutanecarbonitrile (49c)

Colorless oil (8.55 g, 65%). ¹H NMR (300 MHz, CDCl₃): δ 2.02 (2H, m);2.25 (2H, m); 2.81 (2H, m); 5.08 (2H, s); 6.95 (2H, broad d); 7.32 (7H,m).

1-[4-(4-methoxybenzyloxy)phenyl]cyclobutanecarbonitrile (49d)

Yellow solid (8.90 g, 61%). ¹H NMR (400 MHz, CDCl₃): δ 2.03 (2H, m);2.59 (2H, m); 2.78 (2H, m); 3.80 (3H, s); 5.97 (2H, s); 6.94 (4H, m);7.33 (4H, m).

Example 2 General Procedure for Synthesis of 52a-d (Scheme 7)

To a stirred solution of 2M isobutyl magnesium bromide in diethyl ether(0.04 mole, 20 mL) under nitrogen atmosphere at room temperature wasdropwise added a solution of appropriate cyclobutanenitrile 49a-d (0.025mole) in 20 mL of anhydrous THF or toluene. The resulting mixture wasrefluxed for 18-24 hours. The progress of the reaction was monitored byTLC. In a separate round bottom flask 25 mL of anhydrous isopropanol wastaken and sodium borohydride (3.00 g, 0.08 mole) was added toisopropanol portion-wise at room temperature. After having stirred for10 minutes, the Grignard adduct from the reaction flask was directlyadded into the stirred solution sodium borohydride in isopropanol undernitrogen atmosphere. The resulting mixture was refluxed for 12 to 18hours. The progress of the reaction was monitored by TLC. The reactionmixture was slowly poured onto a mixture of crushed ice (200 g) andsodium bicarbonate (5.00 g). The mixture was extracted with ethylacetate (100 mL×3). The combined extract was washed with brine (100mL×2), dried over sodium sulfate (Na₂SO₄) and evaporated under reducedpressure to give the corresponding phenylcyclobutane amines 52a-d whichwere purified by silica gel column chromatography technique using 0-100%gradient of ethyl acetate and hexane in good yields. The pure amine52a-d gave satisfactory ¹H NMR and/or mass spectral data.

1-[1-(4-Chlorophenyl)cyclobutyl]-3-methylbutan-1-amine (52a)

Colorless oil (5.60 g, 89%). ¹H NMR (400 MHz, CDCl₃): δ 0.77 (3H, d, J=4Hz); 0.84 (3H, d, J=4 Hz); 1.60 (2H, m); 1.75 (1H, m); 1.90 (2H, m);2.11 (2H, m); 2.55 (4H, m); 2.94 (1H, m); 7.01 (2H, d, J=4.1 Hz); 7.19(2H, d, J=4.1 Hz).

4-[1-(1-Amino-3-methylbutyl)cyclobutyl]phenol (52b)

The compound 52b was prepared from the intermediate 67 as described inthe Step 2 of Example 11 (Scheme 11). The compound 67 was treated withtrifluoroacetic acid in dichloromethane at room temperature for 8 hoursas described in the procedure for synthesis of compound 70 in the Step 4of Example 11 (Scheme 11). The compound was isolated as light yellowcolor liquid in 73% yield. ¹H NMR (400 MHz, CDCl₃): δ 0.78 (3H, broads); 0.84 (3H, broad s); 1.61 (1H, m); 1.83 (2H, m); 1.93 (2H, m); 2.28(2H, m); 2.45 (2H, m); 2.67 (2H, m); 3.22 (1H, m); 6.73 (2H, d, J=4 Hz);7.14 (2H, d, J=4 Hz). MS (ESI): m/z=234.10 (M+H⁺).

1-[1-(4-tert-Butyldimethylsilyloxy)phenyl)cyclobutyl]-3-methylbutan-1-amine(52c)

Colorless oil (6.80 g, 79%). ¹H NMR (400 MHz, CDCl₃): δ 0.25 (6H, s);0.69 (3H, d, J=4 Hz); 0.77 (3H, d, J=4 Hz); 0.82 (9H, s); 1.54 (3H, m);1.65 (2H, m); 1.78 (2H, m); 2.00 (2H, m); 2.17 (2H, m); 2.80 (1H, m);6.60 (2H, d, J=4 Hz); 6.82 (2H, d, J=4 Hz). MS (ESI): m/z=348.10 (M+H⁺).

1-[1-(4-(benzyloxy)phenyl)cyclobutyl]-3-methylbutan-1-amine (52d)

Colorless oil (5.25 g, 65%). ¹H NMR (300 MHz, CDCl₃): δ 0.90 (3H, d, J=4Hz); 0.96 (3H, d, J=4 Hz); 1.61 (3H, m); 2.09 (2H, m); 2.21 (2H, m);2.58 (2H, m); 2.80 (3H, m); 5.09 (2H, s); 6.90 (2H, broad d); 7.34 (3H,m); 7.01 (4H, m).

1-[1-(4-(4-Methoxybenzyloxy)phenyl)cyclobutyl]-3-methylbutan-1-amine(5e)

Colorless oil (5.00 g, 57%). ¹H NMR (300 MHz, CDCl₃): δ 0.88 (3H, d, J=4Hz); 0.94 (3H, d, J=4 Hz); 1.69 (3H, m); 1.98 (2H, m); 2.18 (1H, m);2.36 (4H, m); 3.00 (1H, m); 3.77 (3H, s); 5.31 (2H, s); 6.71-7.01 (8H,m). MS (ESI): m/z=354.00 (M+H⁺).

Example 3 General Procedure for Synthesis of 54a-e (Scheme 7)

To a stirred suspension of cesium carbonate (Cs₂CO₃) (1.30 g, 0.004Mole) in 20 mL of anhydrous N,N-dimethylformamide (DMF) under nitrogenatmosphere at room temperature was added tetrabutylammonium iodide(TBAI) (1.47 g, 0.004 mole) followed by appropriate cyclobutane amine52a-d (0.0035 mole). After having stirred for 30 minutes, a solution ofappropriate bromoalkylcarboxylic esters 53 in 5 mL of DMF was introducedinto the reaction mixture dropwise. The resulting mixture was stirredfor 18-24 hours and the progress of the reaction was monitored by TLC.The reaction mixture was diluted with ethyl acetate (50 mL), filteredthrough a CELITE® pad and washed the CELITE® pad with ethyl acetate (15mL×3). The combined filtrate was washed with brine (50 mL), water (50mL), dried over sodium sulfate (Na₂SO₄) and evaporated. The residue waspurified by silica gel column chromatography technique using 0-50%gradient of ethyl acetate and hexane to give the corresponding amine 54in good yield. The cyclobutane amines 54a-e gave satisfactory ¹H NMRand/or mass spectral data.

Ethyl 2-(1-(1-(4-chlorophenyl)cyclobutyl)-3-methylbutylamino]acetate(54a)

Colorless oil (0.69 g, 59%). ¹H NMR (400 MHz, CDCl₃): δ 0.80 (3H, d, J=4Hz); 0.84 (3H, d, J=4 Hz); 1.25 (3H, t, J=4.25 Hz); 1.60 (2H, m); 1.78(1H, m); 2.19 (2H, m); 2.27 (2H, m); 2.36 (2H, m); 2.75 (1H, m); 3.48(2H, s); 4.16 (2H, q, J=4.25 Hz); 7.16 (2H, d, J=4 Hz); 7.23 (2H, d, J=4Hz). MS (ESI): m/z=338.00 (M+H⁺)

Ethyl 2-(1-(1-(4-chlorophenyl)cyclobutyl)-3-methylbutylamino]butanoate(54b)

Colorless oil (1.10 g, 84%). ¹H NMR (400 MHz, CDCl₃): δ 0.82 (3H, d, J=4Hz); 0.85 (3H, d, J=4 Hz); 1.24 (3H, t, J=4.25 Hz); 1.60 (2H, m); 1.71(3H, m); 1.88 (2H, m); 2.02 (1H, broad s); 2.15 (2H, m); 2.23 (2H, m);2.38 (2H, m); 2.76 (3H, m); 4.10 (2H, q, J=4.25 Hz); 7.14 (2H, d, J=4Hz); 7.24 (2H, d, J=4 Hz). MS (ESI): m/z=366.20 (M+H⁺)

Isopropyl2-(1-(1-(4-chlorophenyl)cyclobutyl)-3-methylbutylamino]butanoate (54c)

Colorless oil (1.05 g, 80%). ¹H NMR (300 MHz, CDCl₃): δ 0.83 (3H, broads); 0.85 (3H, broad s); 1.24 (3H, broad s); 1.26 (3H, broad s); 1.67(3H, m); 1.94 (4H, m); 2.00 (3H, m); 2.21 (4H, m); 2.36 (3H, m); 2.85(1H, m); 5.02 (1H, m); 7.05 (2H, broad d); 7.29 (2H, broad d). MS (ESI):m/z=382.10 (M+H⁺)

Isobutyl2-(1-(1-(4-chlorophenyl)cyclobutyl)-3-methylbutylamino]butanoate (54d)

Colorless oil (1.15 g, 83%). ¹H NMR (300 MHz, CDCl₃): δ 0.94 (6H, broads); 0.97 (6H, broad s); 1.61 (2H, m); 1.76 (2H, m); 1.94 (4H, m); 2.20(3H, m); 2.42 (2H, m); 2.53 (2H, m); 2.80 (1H, m); 3.87 (2H, broad d);7.16 (2H, broad d); 7.27 (2H, broad d). MS (ESI): m/z=394.20 (M+H⁺).

Benzyl 2-(1-(1-(4-chlorophenyl)cyclobutyl)-3-methylbutylamino]butanoate(54e)

Colorless oil (1.13 g, 76%). ¹H NMR (300 MHz, CDCl₃): δ 0.80 (3H, d, J=4Hz); 0.85 (3H, d, J=4 Hz); 1.58 (1H, m); 1.73 (2H, m); 1.84 (2H, m);2.18 (4H, m); 2.33 (1H, m); 2.49 (4H, m); 2.72 (2H, m); 3.44 (1H, m);5.11 (2H, broad s); 7.13 (2H, d, J=5.25 Hz); 7.24 (2H, d, J=5.25 Hz);7.33 (5H, m). MS (ESI): m/z=428.30 (M+H⁺).

Ethyl 2-(1-(1-(4-chlorophenyl)cyclobutyl)-3-methylbutylamino]pentanoate(54f)

Colorless oil (1.17 g, 88%). ¹H NMR (400 MHz, CDCl₃): δ 0.81 (3H, d, J=4Hz); 0.86 (3H, d, J=4 Hz); 1.24 (3H, t, J=4.5 Hz); 1.47 (2H, m); 1.60(2H, m); 1.78 (3H, m); 1.88 (4H, m), 2.31 (3H, m); 2.78 (2H, m); 3.17(1H, m); 4.12 (2H, q, J=4.25 Hz); 7.14 (2H, d, J=5 Hz); 7.23 (2H, d, J=5Hz). MS (ESI): m/z=380.3 (M+H⁺).

Example 4 Alternate Route for the Synthesis of 54a (Scheme 8)

To a stirred solution of cyclobutane amine 52a (0.68 g, 0.0027 mole) andethyl glyoxylate (50% solution in toluene) (1.02 g, 0.01 mole) in 20 mLof a mixture of solvents DMF and acetic acid (ratio, 99:1) was addedsodium triacetoxyborohydride (2.11 g, 0.01 mole) portion-wise over aperiod of 15 minutes at room temperature. The resulting mixture wasstirred for 8 hours at room temperature and the progress of the reactionwas monitored by TLC. The reaction mixture was poured in to saturatedsodium bicarbonate solution (50 mL) and extracted with ethyl acetate (50mL×3). The combined extract was washed with water (50 mL), dried oversodium sulfate (Na₂SO₄) and evaporated. The residue was purified bysilica gel column chromatography using 0-50% gradient of ethyl acetateand hexane as eluents to give pure 54a as colorless liquid in 45% (0.41g) yield. The ¹H NMR and mass spectral data are identical to thecompound synthesized using the protocol described for the synthesis of54a-e (Example 3, Scheme 7).

Example 5 Alternate Route for the Synthesis of 14e (Scheme 8)

Step 1. To a stirred solution of cyclobutane amine 52a (2.51 g, 0.01mole) in 50 mL of methanol was added benzaldehyde (1.27 g, 0.012 mole)under nitrogen atmosphere at room temperature. After having stirred for2 hours at room temperature the reaction mixture was cooled to 0° C. andthen, added sodium borohydride (NaBH₄) (0.55 g, 0.15 mole) portion-wiseover a period of 20 min. The reaction mixture was stirred for 5 hoursand the progress of the reaction was monitored by TLC. The reactionmixture was concentrated under vacuum and the residue was diluted withethyl acetate (100 mL). The resulting mixture was washed successivelywith saturated sodium bicarbonate solution (50 mL), water (50 mL×2),dried over sodium sulfate (Na₂SO₄) and evaporated. The residue waspurified by silica gel column chromatography using 0-50% gradient ofethyl acetate and hexane to give the corresponding N-benzyl amine 57 ascolorless liquid in 90% (3.06 g) yield. ¹H NMR (300 MHz, CDCl₃): δ 0.82(3H, broad s); 0.85 (3H, broad s); 1.03-1.34 (3H, m); 1.67-1.88 (3H, m);2.16-2.46 (4H, m); 2.87 (1H, m); 3.92 (2H, s); 7.24-7.34 (9H, m).

Step 2. To a stirred solution of N-benzylamine 57 (2.56 g, 0.0075 mole)in anhydrous THF (25 mL) was added a 10 M solution of n-butyllithium(n-BuLi) (0.8 mL, 0.008 mole) in hexanes under nitrogen atmosphere at−78° C. The resulting mixture was warmed up to 0° C. The reactionmixture was cooled to −78° C. again and then, added dropwise a solutionof ethyl 5-bromovalerate (3.13 g, 0.01 mole) in THF (10 mL). Thereaction mixture was slowly warmed to room temperature and continuedstirring at room temperature for 5 hours. The progress of the reactionwas monitored by TLC. The reaction mixture was poured onto crushed ice(100 g) and extracted with ethyl acetate (50 mL×3). The combined extractwas washed with water (100 mL), dried over sodium sulfate (Na₂SO₄) andevaporated. The residue was purified by silica gel column chromatographyusing 0-50% gradient of ethyl acetate and hexane as eluent to give thecorresponding amine 58 as colorless liquid in 69% (2.43 g) yield. ¹H NMR(300 MHz, CDCl₃): δ 0.84 (3H, broad d); 0.87 (3H, broad d); 1.25-1.46(7H, m); 1.50-2.00 (6H, m); 2.34 (4H, m); 3.09 (1H, broad s); 3.89 (2H,s); 4.14 (2H, broad q); 6.78-7.09 (4H, m); 7.35 (5H, m).

Step 3. To a stirred suspension of 10% palladium on carbon (Pd—C) (0.5g) was added a solution of 58 (1.17 g, 0.0025 mole) in ethyl acetate (25mL) followed by few drops of concentrated hydrochloric acid (HCl). Theresulting mixture was stirred under hydrogen gas atmosphere for 12 hoursat atmospheric pressure and the progress of the reaction was monitoredby TLC. The reaction mixture was filtered and the precipitate was washedwith a 1:1 mixture of ethyl acetate and ethanol (15 mL×3). The combinedfiltrate was concentrated under reduced pressure and the residue waspurified by silica gel column chromatography using 0-50% gradient ofethyl acetate and hexane as eluent to give the pure aminoester 54e ascolorless liquid in 81% (0.77 g) good yield. The aminoester 54e gavesatisfactory ¹H NMR and mass spectral data and they are identical to thecompound prepared using the general procedure described in Example 3(Scheme 7).

Example 6 Synthesis of 4-chlorobenzylnitrile 47a (Scheme 7)

The building block 47a was purchased from commercial source.

Example 7 Synthesis of 2-[4-(benzyloxy)phenyl]acetonitrile (47b) (Scheme9)

To a stirred suspension of potassium carbonate (K₂CO₃) (7 g, 0.05 mole)in anhydrous DMF (50 mL) was added 4-hydroxybenzylnitile (59) (6.65 g,0.05 mole) followed by benzylbromide (8.55 g, 0.05 mole). The resultingmixture was heated at 70° C. for 10-12 hours and the progress of thereaction was monitored by TLC. The reaction mixture was diluted withethyl acetate (100 mL) and filtered. The filtrate was washed with water(100 mL×2), dried over magnesium sulfate (MgSO₄) and evaporated underreduced pressure. The residue was purified by silica gel columnchromatography using 0-50% gradient of ethyl acetate and hexane aseluents to give the pure 4-benzyloxybenzylnitrile (47b) as white solidin good 88% (9.82 g) yield. The pure 47b gave satisfactory ¹H and massspectral data. ¹H NMR (300 MHz, CDCl₃): δ 3.70 (2H, s); 5.08 (2H, s);6.98 (2H, broad s); 7.23 (2H, broad s); 7.40 (5H, m). MS (ESI):m/z=223.10 (M+H⁺)

Example 8 Synthesis of 4-(4-methoxybenzyloxy)benzylnitrile (47c) (Scheme9)

4-(4-Methoxybenzyloxy)benzylnitrile (47c) was prepared by following theprotocol described for the synthesis of 47b in 76% (9.60 g).

Example 9 Synthesis of2-[4-(tert-butyldimethylsilyloxy)phenyl]acetonitrile (47d) (Scheme 9)

To a stirred solution of 4-hydroxybenzylnitrile (59) (6.65 g, 0.05 mole)in 75 mL of dichloromethane (DCM) was added imidazole (3.40 g, 0.05mole) and N,N-dimethylaminopyridine (DMAP) (1.2 g, 0.01 mole). Afterhaving stirred for 10 minutes, a solution of tert-butyldimethylsilylchloride (8.29 g, 0.055 mole) in 50 ml of DCM was added dropwise atice-bath temperature. The resulting mixture was stirred for 8 hours andthe progress of the reaction was monitored by TLC. The reaction mixturewas washed with cold water (100 mL×2), dried over magnesium sulfate(MgSO₄) and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography using 0-25% gradient of ethylacetate and hexane as eluents to give the pure 47d as colorless thickliquid in 97% (12.58 g) yield. The pure 47d gave satisfactory ¹H andmass spectral data. ¹H NMR (400 MHz, CDCl₃): δ 0.00 (6H, s); 0.78 (9H,s); 3.47 (2H, s); 6.55 (2H, d, J=5.2 Hz); 6.97 (2H, d, J=5.2 Hz).

Example 10 Synthesis of1-[1-(4-chlorophenyl)cyclobutyl]-3-(1,3-dioxan-2-yl)propan-1-amine (65)(Scheme 10)

The cyclobutanealkyl amine 65 was prepared in good yields by followingthe protocol described for 52a-d in Scheme 7. Colorless oil (79%). ¹HNMR (400 MHz, CDCl₃): δ 1.53-1.85 (6H, m); 1.90-2.06 (2H, m); 2.20-2.34(6H, m); 2.89 (1H, m); 3.72 (2H, m); 4.05 (2H, m); 4.45 (1H, t, J=4 Hz);7.05 (2H, d, J=5.25 Hz); 7.24 (2H, d, J=5.25 Hz). MS (ESI): m/z=310.10(M+H⁺).

Example 11 Synthesis of ethyl2-[4-(1-(1-amino-3-methylbutyl)cyclobutyl)phenoxy]acetate (70) (Scheme11)

Step 1. Synthesis of tent-Butyl1-[1-(4-tert-butyldimethylsilyloxy)phenyl)cyclobutyl]-3-methylbutylcarbamate(66). To a stirred solution of 52d (5.20 g, 0.014 mole) andtriethylamine (TEA) (2 mL, 0.014 mole) in DCM (25 mL) at roomtemperature was added a solution of di-tert-butyl dicarbonate (BOCanhydride) (3.20 g, 0.015 mole) in DCM (25 mL). The resulting mixturewas stirred at room temperature for 12 hours and the progress of thereaction was monitored by TLC. The reaction mixture was diluted with DCM(50 mL), washed with water (50 mL×3), dried over sodium sulfate(Na₂SO₄), and evaporated. The residue was purified by silica gel columnchromatography using 0-25% gradient of ethyl acetate and hexane aseluent to get the pure N—BOC protected amine 66 as colorless liquid in98% (6.30 g) yield. ¹H NMR (400 MHz, CDCl₃): δ 0.27 (6H, s); 0.73 (3H,d, J=4 Hz); 0.80 (3H, d, J=4 Hz); 0.89 (9H, s); 1.45 (9H, broad s);1.50-1.55 (2H, m); 1.62-1.66 (1H, m); 1.75-1.78 (2H, m); 1.91-2.05 (2H,m); 2.17 (2H, m); 3.20 (1H, m); 6.72 (2H, broad d); 6.95 (2H, broad d).MS (ESI): m/z=348.10 (M−BOC).

Step 2. Synthesis of tert-Butyl1-[1-(4-hydroxyphenyl)cyclobutyl]-3-methylbutyl-carbamate (67). Thedeprotection of OTBs group was carried out by following a literatureprotocol (Maiti, G. and Roy, S. C., Tetrahedron Letters 1997, 38, 495).A stirred solution of N—BOC protected amine 66 (2.29 g, 0.005 mole) in20 mL of a mixture of dimethlsulfoxide and water (95:5 ratio) was heatedat 90° C. for 6 hours. The progress of the reaction was monitored byTLC. The reaction mixture was diluted with ethyl acetate (100 mL) andthen, successively washed with brine (50 mL), water (50 mL). The organiclayer was dried over sodium sulfate (Na₂SO₄) and evaporated. The residuewas purified by silica gel column chromatography using 0-50% gradient ofethyl acetate and hexane as eluent to give the pure phenolic derivative67 as colorless liquid in 79% (1.31 g) yield. ¹H NMR (400 MHz, CDCl₃): δ0.78 (3H, broad s); 0.80 (3H, broad s); 1.70 (9H, broad s); 1.52-1.69(3H, m); 2.24 (2H, m); 2.43 (2H, m); 2.78 (2H, m); 3.40 (1H, m); 6.69(2H, broad d); 7.09 (2H, broad d). MS (ESI): m/z=667.00 (2×M+H⁺).

Step 3. Synthesis of ethyl2-[4-(1-(1-(tert-butoxycarbonylamino)-3-methylbutyl)-cyclobutyl)phenoxy]-acetate(69). To a stirred solution of phenol 67 (0.5 g, 0.0015 mole) in 25 mLof anhydrous DMF was added cesium carbonate (Cs₂CO₃). The resultingmixture was heated at 70° C. for 12 hours. The reaction mixture wascooled to room temperature and added ethyl bromoacetate. The reactionmixture was further stirred at 70° C. for 8 hours and the progress ofthe reaction was monitored by TLC. The reaction mixture was diluted withethyl acetate (100 mL), washed with water (50 mL×2), dried overanhydrous sodium sulfate (Na₂SO₄) and evaporated. The residue waspurified by silica gel column chromatography using 0-50% gradient ofethyl acetate and hexane as eluent to give the pure ester 69 ascolorless liquid in 61% (0.38 g) yield. MS (ESI): m/z=420.00 (M+H⁺).

Step 4. Synthesis of ethyl2-[4-(1-(1-amino-3-methylbutyl)cyclobutyl)phenoxy]acetate (70). Asolution of 69 (0.25 g, 0.0005 mole) in 20 mL of 1:1 mixture of DCM andtrifluoroacetic acid (TFA) was stirred at room temperature for 8 hours.The progress of the reaction was monitored by TLC. The reaction mixturewas concentrated under reduced pressure. The residue was diluted withDCM (50 mL), washed with brine (25 mL), dried over sodium sulfate(Na₂SO₄) and evaporated. The residue was purified by 0-100% gradient ofethyl acetate and hexane as eluent to give the pure amine 70 ascolorless oil in 85% (0.13 g) yield. ¹H NMR (400 MHz, CDCl₃): δ 0.85(3H, broad s); 0.83 (3H, broad s); 1.25 (3H, t, J=4.5 Hz); 1.59 (1H, m);1.85 (2H, m,); 1.93 (2H, m); 2.20 (2H, m); 2.42 (2H, m); 2.68 (2H, m);3.21 (1H, m); 4.08 (2H, q, J=4.5 Hz); 5.09 (2H, s); (6.81 (2H, broad d);7.13 (2H, broad d).

Example 12 In Vitro Pharmacology Results

The monoamine transporters inhibitory activities of selected compounds(54b and 54d) are reported herein. The compounds were evaluated at MDSPharma services (22011 Drive SE, Bothell, Wash. 98021, USA) using wellestablished radioligand binding assays protocols (Galli, A. et al., J.Exp. Biol. 1995, 198, 2197-2212; Giros, B. et al., Trends Pharmcol. Sci.1993, 14, 43-49; Gu, H. et al., J. Biol. Chem. 1994, 269(10), 7124-7130;Shearman, L. P. et al, Am. J. Physiol., 1998, 275(6 Pt 1), C1621-1629;Wolf, W. A. et al., J. Biol. Chem. 1992, 267(29), 20820-20825). Thehuman recombinant transporter proteins dopamine (DAT), norepinephrine(NET) and serotonin (SERT) were selected for the in vitro assays. TheCHO-K1 cells expressed with human recombinant dopamine transporter (DAT)(MDS catalog 220320) was used for evaluating the dopamine transporterinhibitory activity. Whereas, MDCK cells expressed with humanrecombinant transporters norepinephrine (NET) (MDS catalog no. 204410)and serotonin (SERT) (MDS catalog no. 274030) were used for evaluatingthe norepinephrine transporter (NET) and serotonin transporter (SERT)inhibitory activities, respectively. The radioligand binding assays werecarried out at four different test concentrations and the testconcentrations were 1 nM, 10 nM, 0.1 μM, and 1 μM.

The assays were carried out in duplicates and the quantitative data arereported as IC50, Ki, and nH. Where presented, IC₅₀ values weredetermined by a non-linear, least squares regression analysis usingMathIQ™ (ID Business Solutions Ltd. UK). Where inhibition constants (Ki)are presented, the Ki values were calculated using the equation of Chengand Prusoff (Cheng, Y., Prusoff, W. H., Biochem. Pharmacol. 1973,22:3099-3108) using the observed IC₅₀ of the tested compound, theconcentration of radioligand employed in the assay and the historicalvalues for the K_(D) of the ligand (obtained experimentally at MDSPharma Services). Where presented, the Hill coefficient (n_(H)),defining the slope of the competitive binding curve, was calculatedusing MathIQ™

The monoamine transporters inhibitory activities of selected compounds(54b and 54d) using radioligand binding assays are reported in followingtable.

Compound Assay IC50 Ki n_(H) 54b DAT 0.0569 μM  0.0452 μM 0.826 54b NET0.121 μM  0.120 μM 0.832 54b SERT 0.140 μM 0.0228 μM 0.677 54d DAT 0.370μM  0.294 μM 0.943 54d NET 0.182 μM  0.180 μM 1.04 54d SERT 0.415 μM0.0676 μM 0.578

All printed patents and publications referred to in this application arehereby incorporated herein in their entirety by this reference.

While the preferred embodiment of the invention has been illustrated anddescribed, it will be appreciated that various changes can be madetherein without departing from the spirit and scope of the invention.

1. A method of treating obesity or obesity related co-morbid indication, the method comprising administering to a patient a composition comprising a cycloalkylmethylamine derivative of structural Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, 2, 3, 4, or 5; SP is a direct bond or a spacer selected from O, S, alkyl, acylamino, alkoxy, alkylamino, alkylthio, or amino; X is O, S, NH, or N-alkyl; R² is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally R² and either R⁵ or R⁷ together with the atoms to which R² and R⁵ or R⁷, form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring which is optionally fused to an aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring; R⁴ is hydrogen, alkyl, or substituted alkyl; R⁵ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl; acyl, acylamino, alkoxy, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkylamino, alkylamino, alkylsulfonyl, alkylsulfinyl, alkylthio, amino, arylalkoxy, arylalkoxycarbonylalkoxy, arylalkoxycarbonylalkylamino, aryloxycarbonyl, aryloxycarbonylalkoxy, carbamoyl, carbamate, carboxy, cyano, dialkylamino, ester, halo, heteroalkoxy, hydroxy, or phosphate; or optionally R⁵ and R⁷ together with the atoms to which R⁵ and R⁷, form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring which is optionally fused to an aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring; R⁶ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl; and R⁷ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally R⁵ and R⁷ together with the atoms to which R⁵ and R⁷ are attached, form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring which is optionally fused to an aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring.
 2. The method of claim 1, wherein the obesity or obesity related co-morbid indication is nausea, emesis, cognitive dysfunctions, Alzheimer's disease, eating disorders, irritable bowel syndrome, obsessive compulsive disorders, platelet adhesion; sleep apnea, hyperactivity disorders, schizophrenia, depression, anxiety, male and female sexual function disorders, restless leg syndrome, osteoarthritis, substance abuse, narcolepsy, pain, migraines, cerebral function disorder, premenstrual syndrome, or incontinence.
 3. The method of claim 1, wherein n is 0, 1 or
 2. 4. The method of claim 3, wherein R⁴ is H.
 5. The method of claim 1, wherein the spacer is O, S, alkyl, acylamino, alkoxy, alkylamino, alkylthio, or amino.
 6. The method of claim 5, wherein the spacer is alky or substituted alkyl.
 7. The method of claim 1, wherein R² is substituted phenyl or aryl.
 8. The method of claim 7, wherein R² is phenyl, and the phenyl group is substituted with a halogen, lower alkyl, substituted alkyl, hydroxyl, alkoxy, or a substituent comprising a soft moiety.
 9. The method of claim 1, wherein R² is alkyl.
 10. The method of claim 9, wherein the alkyl is ethyl, n-propyl, iso-propyl or n-butyl, isobutyl, s-butyl, or t-butyl.
 11. The method of claim 9, wherein the alkyl is n-butyl or isobutyl.
 12. The method of claim 1, wherein R⁷ is H, alkyl, substituted alkyl, or an alkyl substituent comprising a soft moiety.
 13. The method of claim 1, wherein R² is (CH₂)_(m)C(O)Oalkyl and m is 0, 1, 2, 3, 4, 5, 6, or
 7. 14. The method of claim 1, wherein n is 0 or 1, R⁵ is halo, and R² is lower alkyl or isobutyl.
 15. The method of claim 1, wherein the spacer is alky or substituted alkyl.
 16. The method of claim 1, wherein R⁷ is H or lower alkoxy.
 17. The method of claim 1, wherein n is 1, R² is lower alkyl or isobutyl, R⁵ is halo or lower alkoxy, and R⁷ is halo or lower alkoxy.
 18. The method of claim 1, wherein R⁷ is halo.
 19. The method of claim 1, wherein the carbon denoted with the * is in the R configuration.
 20. The method of claim 1, wherein the carbon denoted with the * is in the S configuration.
 21. The method of claim 1, wherein the carbon denoted with the * is in a combination of R and S configurations. 